naloxone and Chronic-Disease

Opioid addiction rates are at a national high, with significant morbidity and mortality. In women, rates have been steadily increasing to be at par with addiction rates in men. Women tend to have quicker addiction and shorter duration to adverse outcomes. Treatment of women has the best outcomes when it is gender-specific, trauma-informed, connected with access to psychiatric services, and integrated into the medical home. Improved outcomes can be achieved with coordinated systems of care based on the harm-reduction model, with integration of medication-assisted therapy in a patient-centered medical home.

Topics: Buprenorphine; Chronic Disease; Female; Humans; Naloxone; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Primary Health Care; Risk Factors; Women's Health

Despite proven analgesic efficacy, opioid use is associated with frequently dose-limiting bowel dysfunction that seriously impacts patients' quality of life (QoL). Agents used at present to manage opioid-induced constipation do not address the underlying opioid receptor-mediated cause of bowel dysfunction and are often ineffective. There is, therefore, a significant need for more effective treatment options. The combination of the strong opioid oxycodone and the opioid antagonist naloxone has the potential to prevent opioid-induced bowel dysfunction (OIBD) while maintaining analgesic efficacy.. To review the safety and efficacy of oral prolonged-release (PR) oxycodone/naloxone in the treatment of patients experiencing chronic pain.. A MEDLINE search was done (January 2002 - July 2009) for available literature for prolonged release oxycodone and naloxone in different patient groups. Results were limited to English-language and clinical trials. Data were also obtained from congress materials. WHAT KNOWLEDGE THE READER WILL GAIN: Unmet needs of opioid pain treatment in terms of OIBD, reduced QoL and low treatment compliance, leading to reduced efficacy. A data overview demonstrates the efficacy and tolerability of PR oxycodone/naloxone in the management of severe chronic pain without the burden of severe gastrointestinal adverse events. The combined formulation of a highly effective opioid and an antagonist that acts locally to reduce gastrointestinal side effects is expected to simplify pain management.. The combination of PR oxycodone/naloxone offers the potential of maintaining normal bowel function in patients requiring opioid therapy--it is a strong analgesic that is well tolerated.

Topics: Administration, Oral; Chronic Disease; Clinical Trials as Topic; Constipation; Drug Administration Schedule; Drug Therapy, Combination; Humans; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Quality of Life; Receptors, Opioid; Safety

During the past two decades, systemic μ-opioid receptor antagonists (MORA) have been used in the treatment of various forms of chronic pruritus. In a number of case reports, case series, and controlled trials, treatment with MORA has demonstrated considerable antipruritic effects. In double-blind controlled studies, significant antipruritic relief has been achieved by MORA in cholestatic pruritus, chronic urticaria, and atopic dermatitis. In case reports and case series, antipruritic efficacy of MORA has been reported in prurigo nodularis, mycosis fungoides, postburn pruritus, aquagenic pruritus, hydroxyethyl starch-induced pruritus, and pruritus of unknown origin. However, most of the evidence remains anecdotal, the design of these trials varies, and comparison of results is difficult. In this review we aim to present an overview of these reports and to assess the evidence for the antipruritic action of the drugs naloxone, nalmefene, and naltrexone, which are currently in use for the treatment of chronic pruritus of different origins. We will also evaluate recommendations for the use of MORA in daily medical practice.

Topics: Administration, Oral; Antipruritics; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Naloxone; Naltrexone; Pruritus; Randomized Controlled Trials as Topic; Receptors, Opioid, mu; Risk Assessment; Severity of Illness Index; Treatment Outcome

Opioid analgesics are the cornerstone of pain management for moderate-to-severe cancer pain and, increasingly, chronic noncancer pain. Despite proven analgesic efficacy, the use of opioids is commonly associated with frequently dose-limiting constipation that seriously impacts on patients' quality of life. Agents currently used to manage opioid-induced constipation (OIC), such as laxatives, do not address the underlying opioid receptor-mediated cause of constipation and are often ineffective. A significant need therefore exists for more effective treatment options. A novel approach for selectively and locally antagonizing the gastrointestinal effects of opioids involves the coadministration of a mu-opioid receptor antagonist with negligible systemic availability, such as oral naloxone. Combination therapy with prolonged-release (PR) oxycodone plus PR naloxone has been shown to provide effective analgesia while preventing or reducing constipation. The current article highlights this novel strategy in its potential to significantly improve the quality of life of patients suffering from chronic pain, affording patients the benefit of full analgesia, without the burden of OIC.

Topics: Analgesics, Opioid; Chronic Disease; Clinical Trials as Topic; Constipation; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Laxatives; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Quality of Life

Forty cancer patients were randomly assigned to two groups (n = 20). All had incapacitating pain unresponsive to the usual non opioid analgesic drugs. An epidural catheter was set up at the level of the most painful metamere, and made to pass subcutaneously so as to exit either in the supraclacicular fossa, or on the patient's flank. At T0, the patients were given 4 mg morphine hydrochloride diluted in 10 ml normal saline. Thirty min later, patients in the naloxone group (group N) were given a 0.4 mg bolus, followed by a constant rate infusion of 5 micrograms.kg-1.h-1, of naloxone hydrochloride during 18 h. Patients in group P (placebo) were given normal saline instead. The degree of pain was studied with a visual analogue scale and analgesia was assessed by a clinician on a five point scale. These two parameters were obtained half an hour after the injection of morphine and 2, 4, 6 and 24 hours later. At the same time, the patients were questioned about adverse side-effects: nausea, vomiting, pruritus, dysuria, urinary retention. Respiratory depression was assessed clinically and biologically (blood gas measurements at the afore mentioned times). Heart rate, systolic and diastolic blood pressure were also measured. There was no statistically significant difference between the groups in quality and duration of analgesia. Pain reached its lowest level 4 h after the injection of morphine, returning to half its original value at the 24th h. This was also true for the incidence of nausea (11 in group N, 5 in group P), vomiting (3 in both groups), and urinary retention (6 in group P, 5 in group N).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Analgesia, Epidural; Chronic Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphine; Naloxone; Nausea; Neoplasms; Pain; Pain Measurement; Pruritus; Respiration Disorders; Urinary Retention; Vomiting

In the runner study, as measured by tourniquet ischemic pain, exercise stress produced hypoalgesia 20 minutes post-run, followed by hyperalgesia and euphoria at 30 minutes. The hypoalgesia and euphoria were reversed by naloxone. Exercise stress also produced a decrease in P(A), suggesting hypoalgesia to the thermal cutaneous stimulation. However, this analgesia was not naloxone reversible. Nor did exercise stress produce analgesia to cold-pressor pain. In the acupuncture study, noxious electrical stimulation of classical acupuncture sites failed to produce analgesia either during or after stimulation. However, expectation did produce a change in the pain report criterion, but only in the acupunctured arm. Noxious electrical stimulation (TENS) of the median nerve produced no analgesia outside of the related segmental area, that is, acute electrical pain did not produce generalized hypoalgesia. Thus, the effects of the stress produced by noxious electrical stimulation differ from that produced by exercise. In contrast to the results of the acute pain studies, chronic clinical pain, which combines mental stress and pain stress, produced strong hypoalgesia and anesthesia. Again, in contrast to the acute experimental pain studies, the emotional stress of mental illness produces hypoalgesia, but not anesthesia. Finally, the somatosensory system is not the only the sensory system affected by stress. Cold-pressor pain decreases visual sensitivity both during and for a few minutes following stimulation, and does not interfere with short-term (supra-digit span) memory.

Topics: Acupuncture Therapy; Acute Disease; Adult; Back Pain; Chronic Disease; Cold Temperature; Discrimination Learning; Electric Stimulation; Emotions; Female; Hormones; Hot Temperature; Humans; Ischemia; Male; Memory; Mental Disorders; Naloxone; Pain; Physical Exertion; Sensory Thresholds; Stress, Physiological; Visual Perception

Topics: Acute Disease; Anesthesia; Animals; Blood Circulation; Chronic Disease; Endorphins; Halothane; Humans; Ketamine; Naloxone; Pain; Receptors, Opioid; Shock; Sleep; Thiopental

The aim of this study was to assess safety and efficacy of fixed combination oxycodone prolonged release (PR)/naloxone PR in terms of both analgesia and improving opioid-induced bowel dysfunction (OIBD) and associated symptoms, such as opioid-induced constipation (OIC), in adults with chronic non-cancer pain.. These were open-label extension studies in which patients who had previously completed a 12-week, double-blind study received oxycodone PR/naloxone PR for up to 52 weeks. The analgesia study assessed pain using the modified Brief Pain Inventory-Short Form (BPI-SF). The bowel function study assessed improvements in constipation using the Bowel Function Index (BFI).. At open-label baseline in the analgesia study (n = 379), mean score [+/- standard deviation (SD)] for the BPI-SF item 'average pain over the last 24 h' was 3.9 +/- 1.52, and this remained low at 6 months (3.7 +/- 1.59) and 12 months (3.8 +/- 1.72). Mean scores for BPI-SF item 'sleep interference', and the BPI-SF 'pain' and 'interference with activities' subscales also remained low throughout the 52-week study. In the bowel function study (n = 258), mean BFI score (+/- SD) decreased from 35.6 +/- 27.74 at the start of the extension study to 20.6 +/- 24.01 after 12 months of treatment with oxycodone PR/naloxone PR. Pain scores also remained low and stable during this study. Adverse events in both extension phases were consistent with those associated with opioid therapy; no additional safety concerns were observed.. Results from these two open-label extension studies demonstrate the long-term efficacy and tolerability of fixed combination oxycodone PR/naloxone PR in the treatment of chronic pain. Patients experienced clinically relevant improvements in OIBD while receiving effective analgesic therapy.

Topics: Aged; Analgesics, Opioid; Chronic Disease; Constipation; Defecation; Delayed-Action Preparations; Double-Blind Method; Drug Combinations; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Treatment Outcome

Two randomised 12-week, double-blind, parallel-group, multicenter studies comparing oxycodone PR/naloxone PR and oxycodone PR alone on symptoms of opioid-induced bowel dysfunction in patients with moderate/severe non-malignant pain have been conducted.. These studies were prospectively designed to be pooled and the primary outcome measure of the pooled data analysis was to demonstrate non-inferiority in 12-week analgesic efficacy of oxycodone PR/naloxone PR versus oxycodone PR alone. Patients with opioid-induced constipation were switched to oxycodone PR and then randomised to fixed doses of oxycodone PR/naloxone PR (n = 292) or oxycodone PR (n = 295) for 12 weeks (20-80 mg/day).. No statistically significant differences in analgesic efficacy were observed for the two treatments (p = 0.3197; non-inferiority p < 0.0001; 95% CI -0.07, 0.23) and there was no statistically significant difference in frequency of analgesic rescue medication use. Improvements in Bowel Function Index score were observed for oxycodone PR/naloxone PR by Week 1 and at every subsequent time point (-15.1; p < 0.0001; 95% CI -17.3, -13.0). AE incidence was similar for both groups (61.0% and 57.3% of patients with oxycodone PR/naloxone PR and oxycodone PR alone, respectively).. Results of this pooled analysis confirm that oxycodone PR/naloxone PR provides effective analgesia and suggest that oxycodone PR/naloxone PR improves bowel function without compromising analgesic efficacy.. ClinicalTrials.gov identifier: NCT00412100 and NCT00412152.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chronic Disease; Clinical Trials as Topic; Constipation; Delayed-Action Preparations; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Patient Discharge; Safety; Treatment Outcome; Young Adult

This randomised, double-blind, double-dummy, parallel-group multicentre study assessed the impact of a total daily dose of 60-80 mg oral oxycodone prolonged-release (PR)/naloxone PR (OXN PR) as fixed-ratio combination for patients with opioid-induced constipation (OIC) having moderate-to-severe, non-malignant pain.. During pre-randomisation patients receiving opioids for moderate-to-severe non-malignant pain were converted to oxycodone PR (OXY PR) and titrated to an effective analgesic dose. During randomisation 265 patients on a stable OXY PR dose (60-80 mg/day) and with OIC were included in the full analysis population to receive OXN PR or OXY PR alone. Primary outcome was improvement in symptoms of constipation as measured by the Bowel Function Index (BFI). Secondary/exploratory outcomes examined analgesic efficacy and other bowel function parameters.. After 4 weeks of treatment, patients receiving OXN PR showed a significant improvement in bowel function compared with those in the OXY PR group (-14.9; 95% CI: -17.9, -11.9; p<0.0001) as measured by BFI which was seen after only 1 week of treatment continuing to the end of the study. After 4 weeks of treatment, patients receiving OXN PR had a median number of 3.0 complete spontaneous bowel movements (CSBM) per week compared with only 1.0 for OXY PR alone. Laxative intake was lower in the OXN PR than the OXY PR group. Furthermore, improvements in bowel function were achieved without loss of analgesic efficacy; pain intensity scores were comparable between the groups and consistent for duration of the study. Most frequently reported adverse events were consistent with those reported for opioid analgesics; no new or unexpected adverse reactions attributable to OXN PR used in higher doses were observed.. This study shows that the fixed-ratio combination of OXN PR is superior to OXY PR alone in terms of bowel function, while providing effective equivalent analgesia.

Topics: Analgesics, Opioid; Chronic Disease; Constipation; Delayed-Action Preparations; Drug Combinations; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Treatment Outcome

The Bowel Function Index (BFI) is a clinician-administered, patient-reported, 3-item questionnaire to evaluate opioid-induced constipation in cancer and non-cancer chronic pain patients. The objective of the present analysis was to evaluate the psychometric characteristics of the BFI using data from clinical studies of oral prolonged release (PR) oxycodone/naloxone.. OXN2401 was a multicenter, controlled, randomized, double-blind, parallel-group study including oral PR oxycodone combined with oral PR naloxone as well as oral PR oxycodone combined with corresponding naloxone placebo. OXN3401 and OXN3001 were 12-week multicenter, controlled, randomized, double-blind, parallel-group studies of a fixed combination of oral PR oxycodone/naloxone versus PR oxycodone. In addition, a placebo group was included in study OXN3401. BFI psychometric characteristics (reliability, reproducibility, convergent/known groups validity, and responsiveness) were evaluated.. Demographic data (n=985) were comparable and analyses indicated a high degree of internal consistency (Cronbach's alpha >0.7). Change of less than 5 points in BFI was indicative of high reproducibility. Correlations between BFI item and total scores to stool frequency were statistically significant and in the low-to-moderate range (OXN2401 -0.23 to -0.29, p < 0.001; OXN3401 range -0.26 to -0.40, p < 0.001; OXN3001 -0.14 to -0.15, p < 0.05). Data indicate that a BFI score change of ≥12 points represents a clinically meaningful change in constipation.. This publication for validation of BFI only includes data from three clinical trials. However, another publication of an additional specifically designed cross-sectional validation study is in preparation.. The BFI is a valid and reliable instrument for the assessment of opioid-induced constipation in chronic pain patients. Psychometric analyses from clinical trials support the BFI's psychometric properties.

Topics: Analgesics, Opioid; Chronic Disease; Constipation; Delayed-Action Preparations; Diagnostic Self Evaluation; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Reproducibility of Results; Severity of Illness Index; Surveys and Questionnaires

Opioid-induced constipation can have a major negative impact on patients' quality of life. This randomised clinical trial evaluated patient assessment of the efficacy and tolerability of oral prolonged-release (PR) oxycodone when co-administered with oral naloxone PR.. Two hundred and two patients with chronic cancer- or non-cancer-related pain undergoing stable oxycodone PR therapy (40, 60 or 80 mg/day) were randomised to one of four intervention groups: 10, 20 or 40 mg/day naloxone PR or placebo. Following a 4-week maintenance phase, patients were followed-up for 2 weeks in which time they received oxycodone PR only. At the end of the maintenance phase, patients and investigators were asked to assess treatment efficacy and tolerability, as well as preference for the titration or maintenance phase.. Patient and investigator global assessment of efficacy and tolerability improved with increasing naloxone dose. Efficacy was ranked as 'good' or 'very good' by 50.0%, 67.4% and 72.5% of patients in the 10, 20 and 40 mg naloxone PR dose groups, respectively, compared with 43.5% of patients in the placebo group. Patient assessment of tolerability was similar between treatment groups and placebo, being ranked as 'good' or 'very good' by 83.3%, 79.1% and 82.5% of patients in the 10, 20 and 40 mg/day naloxone PR dose groups, respectively, compared with 71.7% of patients in the placebo group. The maintenance treatment phase was preferred by patients in the naloxone groups. A 2 : 1 dose ratio of oxycodone to naloxone was also assessed. Efficacy was ranked as 'good' or 'very good' by 70.4% of patients treated with the 2 : 1 dose ratio compared with 43.5% of patients receiving placebo. Tolerability of the 2 : 1 dose ratio was ranked as being 'good' or 'very good' by 81.5% of patients compared with 71.1% for the placebo group and patients preferred the maintenance phase.. The co-administration of oral naloxone PR with oxycodone PR improves patient assessment of analgesic opioid therapy for severe chronic pain, in terms of both efficacy and tolerability.

Topics: Adolescent; Adult; Aged; Analgesics, Opioid; Chronic Disease; Constipation; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Pain Measurement; Patient Satisfaction; Prospective Studies; Severity of Illness Index; Treatment Outcome

This randomized, double-blind, placebo- and active-controlled, parallel-group study was designed to demonstrate the superiority of oxycodone in combination with naloxone in a prolonged release (PR) formulation over placebo with respect to analgesic efficacy. The active control group was included for sensitivity and safety analyses, and furthermore to compare the analgesic efficacy and bowel function of oxycodone PR/naloxone PR with oxycodone PR alone. The analgesic efficacy was measured as the time from the initial dose of study medication to multiple pain events (ie, inadequate analgesia) in patients with moderate to severe chronic low back pain. The full analysis population consisted of 463 patients. The times to recurrent pain events were significantly longer in the oxycodone PR/naloxone PR group compared with placebo (P < .0001-.0003); oxycodone PR/naloxone PR reduced the risk of pain events by 42% (P < .0001; full analysis population). The appearance of pain events was comparable for oxycodone PR/naloxone PR versus oxycodone PR, confirming that the addition of naloxone PR to oxycodone PR in a combination tablet did not negatively affect analgesic efficacy of the opioid. Furthermore, oxycodone PR/naloxone PR offers benefits in terms of an improvement in bowel function. In a therapeutic area of great unmet need, therefore, the combination tablet of oxycodone PR/naloxone PR offers patients effective analgesia while improving opioid-induced bowel dysfunction. Taken together with the observation that the safety profile of oxycodone PR/naloxone PR is consistent with that expected from other opioid analgesics except opioid-induced constipation, these findings indicate that the addition of naloxone to oxycodone in a PR combination tablet offers improved tolerability. Oxycodone PR/naloxone PR is therefore a promising new treatment approach for the management of chronic pain.. This study evaluated the analgesic efficacy and safety of the combination of oxycodone PR/naloxone PR in chronic nonmalignant pain. Opioids are often reduced in dosage or even discontinued as a result of impaired bowel function, leading to insufficient pain treatment. Not only does oxycodone PR/naloxone PR demonstrate analgesic efficacy comparable with oxycodone PR, but it also improves opioid-induced bowel dysfunction, and may therefore improve the acceptability of long-term opioid treatment for chronic pain.

Topics: Analgesics, Opioid; Chronic Disease; Constipation; Delayed-Action Preparations; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Low Back Pain; Male; Naloxone; Narcotic Antagonists; Oxycodone; Pain Measurement; Severity of Illness Index; Time Factors; Treatment Outcome

A family history of chronic pain has previously been linked to increased incidence of spontaneous acute pain and risk for chronic pain. Mechanisms underlying these associations are unknown, although similar effects on both acute and chronic pain suggest that central endogenous analgesic system differences may be relevant. This study tested whether a positive parental chronic pain history (PH+) was associated with impaired endogenous opioid analgesic responses to acute pain. Seventy-three chronic low back pain patients (LBP) and 46 pain-free controls received opioid blockade (8mg naloxone i.v.) and placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each, subjects participated in a 1-min finger pressure pain task followed by an ischemic forearm pain task, providing pain intensity ratings during and immediately following each task. To assess opioid analgesic function, blockade effects were derived by subtracting placebo from blockade condition pain responses. Placebo condition analyses indicated that both PH+ subjects and LBP subjects reported greater acute pain sensitivity than respective comparison groups (p's<.05). Multivariate analyses indicated that, beyond any influence of current chronic pain status, PH+ subjects failed to exhibit any endogenous opioid analgesia to acute ischemic pain, whereas PH- subjects elicited effective opioid analgesia (p<.05). A significant multivariate PHxSubject Type interaction (p<.05) indicated that opioid analgesic impairments were most prominent in PH+ LBP subjects. Similar analyses for finger pressure pain blockade effects were nonsignificant (p>.10). The possible heritability of endogenous opioid analgesic dysfunction observed in individuals with a positive parental chronic pain history remains to be investigated.

Topics: Adult; Analgesia; Brain Chemistry; Chronic Disease; Cross-Over Studies; Family Health; Female; Humans; Low Back Pain; Male; Medical History Taking; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain Measurement; Pain Threshold; Parents; Placebos

Recent work suggests that an expressive anger management style (anger-out) is associated with elevated acute pain sensitivity due to endogenous opioid antinociceptive dysfunction. We tested the hypothesis that this opioid dysfunction mediates the previously reported positive association between anger-out and chronic pain intensity. To assess endogenous opioid antinociception in the laboratory, 71 subjects with chronic low back pain received opioid blockade (8 mg naloxone i.v.) or placebo in counterbalanced order in separate sessions. During each, subjects participated in a 1-min finger pressure pain task followed by an ischemic forearm pain task, providing acute pain ratings on the McGill Pain Questionnaire-Short Form (MPQ) immediately following each task. Subjects also completed a 7-day chronic pain diary based on the MPQ between laboratory sessions. To index opioid antinociceptive function, blockade effects were derived, subtracting placebo from blockade condition pain ratings. Greater anger-out was associated with both smaller blockade effects (suggesting impaired opioid antinociception) and greater chronic pain intensity, and blockade effects were inversely associated with chronic pain intensity. Sequential hierarchical regressions suggested that opioid dysfunction partially mediates the positive association between anger-out and total MPQ chronic pain intensity. Inclusion of blockade effects in the first step of the regression resulted in a decrease from 7 to 3% in chronic pain variance accounted for by anger-out. Opioid dysfunction did not mediate the positive association between anger-in and chronic pain. These results provide preliminary support for the hypothesis that the positive association between anger expression and chronic pain intensity is mediated by opioid antinociceptive system dysfunction.

Topics: Adult; Anger; Chronic Disease; Cross-Over Studies; Double-Blind Method; Female; Humans; Low Back Pain; Male; Naloxone; Opioid Peptides; Pain Measurement; Regression Analysis

The experience of anger (i.e. trait anger) and anger management style (i.e. anger-in, anger-out) are related to sensitivity to acute and chronic pain stimuli, although underlying mechanisms are unknown. This study tested whether anger variables are associated with impaired endogenous opioid antinociceptive activity, and whether these relationships differed between chronic pain patients and healthy normals. Forty-three chronic low back pain (LBP) sufferers and 45 pain-free normals received opioid blockade (8 mg naloxone i.v.) or placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each session, subjects participated in a 1-min finger pressure pain task followed by an ischemic forearm pain task (maximum duration 5 min), providing pain intensity ratings during and immediately following each task. As a measure of opioid antinociceptive function, drug effects were derived by subtracting placebo from blockade condition pain ratings. Multivariate general linear model analyses indicated that anger-out, but not anger-in, had significant main effects on both finger pressure drug effects (P < 0.05) and ischemic task drug effects (P < 0.05). As hypothesized, high anger-out scores were associated with an absence of opioid analgesia during the acute pain tasks; low anger-out scores were associated with effective opioid analgesia. A similar non-significant trend was noted for trait anger on finger pressure drug effects (P < 0.06). Anger-out x LBP/normal interactions were non-significant, suggesting that links between anger-out and drug effects were similar for patients and normals. Controlling for depression did not eliminate the significant relationship between anger-out and drug effects. Findings suggest that anger-in and anger-out affect pain sensitivity through different mechanisms: only the effects of anger-out may be mediated by endogenous opioid dysfunction.

Topics: Acute Disease; Anger; Chronic Disease; Cross-Over Studies; Depression; Double-Blind Method; Fingers; Humans; Low Back Pain; Multivariate Analysis; Naloxone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Pain Measurement; Pain Threshold; Placebos; Pressure

Resting blood pressure is inversely correlated with acute pain sensitivity in healthy normotensives. This study tested: (1) whether endogenous opioid activity is necessary for this adaptive relationship to occur, (2) whether this relationship is altered in chronic low back pain (LBP), and (3) whether endogenous opioid dysfunction underlies any such alterations. Fifty-one pain-free normotensives and 44 normotensive chronic LBP sufferers received opioid blockade (8 mg naloxone i.v.) or placebo blockade (saline) in randomized, counterbalanced order in separate sessions. During each session, subjects participated in a 1-min finger pressure (FP) pain task followed by an ischemic (ISC) forearm pain task. Among pain-free normotensives, elevated resting systolic (SBP) and diastolic (DBP) blood pressure were associated with significantly higher ISC pain thresholds (P values <0.05). Elevated SBP was also associated with significantly lower FP pain ratings (P<0.05). Opioid blockade had no significant effect on the BP-pain relationships detected (P values >0.10). In combined groups analyses, a significant subject typexSBP interaction (P<0.005) was found on ISC pain threshold: elevated SBP was associated with higher pain threshold in pain-free controls, but with lower pain threshold in LBP subjects. Although subject typexBP interactions on FP and ISC pain ratings were not significant, inclusion of LBP subjects in these analyses resulted in the overall relationship between BP and pain sensitivity becoming positive (P values <0.05). Opioid blockade exerted no significant main or interaction effects in these combined groups analyses (p values >0.10). Higher DBP was associated with greater clinical pain intensity among the LBP subjects (P<0.001). Overall, these results suggest: (1) endogenous opioids do not mediate the inverse relationship between resting blood pressure and acute pain sensitivity in pain-free normotensives; (2) the BP-pain sensitivity relationship is altered in chronic pain, suggesting dysfunction in pain regulatory systems, and (3) these alterations are not related to opioid dysfunction.

Topics: Acute Disease; Adult; Blood Pressure; Chronic Disease; Cross-Over Studies; Double-Blind Method; Female; Humans; Low Back Pain; Male; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain Threshold; Rest

335 patients (51% female, 49% male, mean age 56 years) with chronic pain and multimorbidity have been included in a multi-center 2-years' study with slow release Tilidine/Naloxone for efficacy and safety which included detailed laboratory examinations. 316 patients had already been treated with analgesics. 159 patients (47.5%) finished the study as planned, 176 patients finished the study earlier.. Parameters of quality of life such as persistent pain, sleep, mood and activity have improved. Tolerance has not been observed. In 85 patients (25%) adverse events had occurred (nausea, vomiting, dizziness) which are related to the study-medication. Constipation was documented in only 4 patients. After 2 years of therapy with Tilidine/Naloxone there has been no relevant changes in laboratory findings. There has been no sign of organ damage or interactions with concomitant medication.. Tilidine/Naloxone is an effective and safe analgesic (WHO II) suitable for the longterm treatment of patients with chronic pain.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chronic Disease; Comorbidity; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy, Combination; Female; Humans; Long-Term Care; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Quality of Life; Tilidine; Treatment Outcome

The most common side effect of opioid therapy is constipation. It is often difficult to treat and is believed to be primarily a peripheral effect. Single large doses of oral naloxone have been shown to be efficacious in reversing opioid-induced constipation. However, they often cause the unwanted side effect of analgesia reversal. This study evaluated the effects on constipation and analgesia of low doses of oral naloxone given three times daily. Patients taking stable doses of opioids with complaints of constipation were recruited for this double-blind, randomized, placebo-controlled study. Patients were given 4 mg or 2 mg of oral naloxone, or placebo, three times daily. Stool frequency and symptoms related to constipation were recorded daily. Patients also recorded the daily amount of analgesics required to maintain pain control. Nine patients were recruited for the study. All the patients who received oral naloxone had some improvement in their bowel frequency. Three of the patients also experienced reversal of analgesia, including one who had complete reversal of analgesia. This study demonstrates that reversal of analgesia still occurred despite dividing the oral naloxone into very low doses relative to the total dose of opioid used. Patients using high doses of opioids appear to be the most vulnerable to the analgesic effect of oral naloxone.

Topics: Administration, Oral; Adult; Aged; Analgesia; Analgesics, Opioid; Chronic Disease; Constipation; Double-Blind Method; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Pilot Projects

A series of double-blind, placebo-controlled clinical trials demonstrated that low doses of morphine (0.4, 1.2, and 3.6 mg) administered into the intraligamentary space of a chronically inflamed hyperalgesic tooth produced a dose-related naloxone-reversible analgesia. This analgesic effect is mediated by a local mechanism in the inflamed tissue, because subcutaneous administration of a 1.2 mg dose of morphine failed to elicit an analgesic response. In contrast, submucosal administration of 1.2 mg morphine or 50 microg fentanyl to the site of extraction of an impacted third molar after the onset of acute pain failed to elicit an analgesic response despite demonstration of a sensitive bioassay. These data indicate that peripheral opioid analgesia can be evoked in a model of chronic, but not acute, inflammatory pain, suggesting a temporal dependent mechanism needed for the expression of peripheral opiate analgesia during inflammation in humans.

Topics: Acute Disease; Adult; Analgesics, Opioid; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fentanyl; Humans; Injections; Male; Mepivacaine; Morphine; Naloxone; Pain Measurement; Pain, Postoperative; Periodontitis; Time Factors; Tooth Extraction; Toothache; Treatment Outcome

Opioid-related constipation is one of the most frequent side effects of chronic pain treatment. Enteral administration of naloxone blocks opioid action at the intestinal receptor level but has low systemic bioavailability due to marked hepatic first-pass metabolism. The aim of this study was to examine the effects of oral naloxone on opioid-associated constipation in an intraindividually controlled manner. Twenty-two chronic pain patients with oral opioid treatment and constipation were enrolled in this study. Constipation was defined as lack of laxation and/or necessity of laxative therapy in at least 3 out of 6 days. Laxation and laxative use were monitored for the first 6 days without intervention ('control period'). Then, oral naloxone was started and titrated individually between 3x3 to 3x12 mg/day depending on laxation and withdrawal symptoms. After the 4-day titration period, patients were observed for further 6 days ('naloxone period'). The Wilcoxon signed rank test was used to compare number of days with laxation and laxative therapy in the two study periods. Of the 22 patients studied, five patients did not reach the 'naloxone period' due to death, operation, systemic opioid withdrawal symptoms, or therapy-resistant vomiting. In the 6 day 'naloxone' compared to the 'control period', the mean number of days with laxation increased from 2.1 to 3.5 (P<0.01) and the number of days with laxative medication decreased from 6 to 3.8 (P<0.01). The mean naloxone dose in the 'naloxone period' was 17.5 mg/day. The mean pain intensity did not differ between these two periods. Moderate side effects of short duration were observed in four patients following naloxone single dose administrations between 6 and 20 mg, resulting in yawning, sweating, and shivering. Most of the patients reported mild or moderate abdominal propulsions and/or abdominal cramps shortly after naloxone administration. All side effects terminated after 0.5-6 h. This controlled study demonstrates that orally administered naloxone improves symptoms of opioid associated constipation and reduces laxative use. To prevent systemic withdrawal signs, therapy should be started with low doses and patients carefully monitored during titration.

Topics: Administration, Oral; Analgesics, Opioid; Cathartics; Chronic Disease; Constipation; Humans; Naloxone; Narcotic Antagonists; Neoplasms; Pain

In a canine model of congestive heart failure beta endorphin concentrations were high and opioid receptor antagonists exerted beneficial haemodynamic effects. In humans previous studies have suggested that opioid peptides may modify the perception of breathlessness and fatigue in heart failure.. Plasma concentrations of beta endorphin were measured in patients with acute and chronic heart failure and cardiogenic shock. A subgroup of eight patients with New York Heart Association (NYHA) class III-IV heart failure was assessed for acute haemodynamic effects of naloxone, an opioid receptor antagonist. A separate group of 10 patients with class II-III heart failure, was randomised to a double blind placebo controlled study of the effects of intravenous naloxone on cardiopulmonary exercise performance.. Plasma concentrations of beta endorphin were usually normal in patients with chronic heart failure and did not correlate with severity as assessed by NYHA class. In 29% of patients with acute heart failure and 71% of those with cardiogenic shock beta endorphin concentrations were high. The median concentration in the cardiogenic shock group was significantly higher than in either of the two heart failure groups and there was some evidence of a relation between beta endorphin concentrations and survival. At the doses tested, naloxone was unable to modify systemic haemodynamics, exercise performance, or symptoms in patients with chronic congestive heart failure.. Circulating concentrations of beta endorphin are usually normal in patients with chronic congestive heart failure. Inhibition of the endogenous opioid system is unlikely to have therapeutic potential in heart failure.

Topics: Acute Disease; Adult; Aged; beta-Endorphin; Chronic Disease; Double-Blind Method; Exercise Test; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Naloxone; Shock, Cardiogenic; Stroke Volume; Ventricular Function, Left

Two acromegalic patients with severe headache were treated with the somatostatin analogue, octreotide (Sandostatin). A double-blind study of octreotide versus placebo in which pain intensity was measured using a visual analogue scale (VAS) was performed initially with these patients. A rapid (within 4-15 min) pain relief occurred lasting 2-8.5 h after injection of 100 micrograms of octreotide, an effect that was not reversed by intravenous (i.v.) naloxone. These 2 acromegalic patients then received treatment for 71 and 82 months, respectively, with doses starting at 500 micrograms/day and 1500 micrograms/day, respectively, without evidence of either tolerance or dependence, although the effect of octreotide on headache appears to be selective. No unwanted sedative effect has been observed. A screening procedure with injection of 50 micrograms of subcutaneous (s.c.) octreotide was performed in 11 other patients with chronic severe pain associated with various conditions. Only 3 patients (2 with diabetic polyneuropathy and 1 with bone pain associated with myelodysplastic syndrome) reported more than 50% pain relief. In the insulin-dependent diabetic patients the double-blind check was not performed due to the risk of octreotide-induced hypoglycemia. In the patient with bone pain the same double-blind check as in the acromegalic patients could not confirm the analgesic effect. It may thus be concluded that octreotide appears to be useful for the treatment of both chronic and acute severe painful conditions in acromegalic patients. However, since its analgesic effect in our patients was confined to headaches only, further controlled studies must be carried out in order to determine appropriate target groups.

Topics: Acromegaly; Adult; Analgesics; Chronic Disease; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Headache; Humans; Injections, Subcutaneous; Male; Naloxone; Octreotide; Radiography

To test the hypothesis that opioid agonist activity contributes to the pruritus of cholestasis, a placebo-controlled single-blinded trial of naloxone, an opioid antagonist, was conducted in eight patients with primary biliary cirrhosis. After discontinuation of all conventional antipruritic medications, one or two continuous (24-hour) IV infusions of naloxone (0.2 micrograms.kg-1.min-1) and placebo solution were administered consecutively in an order that was not predetermined. Pruritus was assessed subjectively by means of four hourly recordings of a visual analogue score. In addition, objective measurements of scratching activity that were independent of gross body movements were continuously recorded using an apparatus specifically designed to measure the frequencies associated with this activity. No side effects associated with naloxone infusions were observed. Only scratching activity data obtained for the same periods of day and night during both naloxone and placebo infusions were compared. Naloxone infusions were consistently associated with a decrease in values of the scratching activity index. In addition, in 50% of the patients the infusions were associated with a decrease in visual analogue score. The mean decrease in scratching activity ranged from 29% to 96% (mean, 50%; P less than 0.001). These findings imply that increased opioid agonist activity contributes to scratching activity in cholestatic patients.

Topics: Adult; Aged; Chronic Disease; Female; Humans; Infusions, Intravenous; Liver Cirrhosis, Biliary; Middle Aged; Motor Activity; Naloxone; Pilot Projects; Pruritus; Single-Blind Method

We have studied if 2 Hz electroacupuncture alleviates chronic nociceptive pain and if so whether the alleviation was related to the release of endogenous opioids. Thirty-two patients suffering from osteoarthritis were subjected to electroacupuncture, with or without pretreatment with naloxone or diazepam. The effect of the different experimental procedures was assessed using scales for the intensity (sensory component) and unpleasantness (affective component) of pain. Electroacupuncture induced a significant alleviation of pain. This alleviation was more significant on the affective scales (p less than 0.01) than on the sensory scales (p less than 0.05). After pretreatment with diazepam or naloxone, the subsequent pain alleviating effect was reduced. These data indicate that acupuncture induced analgesia may partly be mediated through endogenous opioids which are affected by pretreatment with diazepam or naloxone.

Topics: Acupuncture Analgesia; Aged; Animals; Chronic Disease; Combined Modality Therapy; Diazepam; Electroacupuncture; Endorphins; Humans; Middle Aged; Naloxone; Osteoarthritis; Pain; Pain Management; Pain Measurement; Receptors, Opioid

Forty cancer patients were randomly assigned to two groups (n = 20). All had incapacitating pain unresponsive to the usual non opioid analgesic drugs. An epidural catheter was set up at the level of the most painful metamere, and made to pass subcutaneously so as to exit either in the supraclacicular fossa, or on the patient's flank. At T0, the patients were given 4 mg morphine hydrochloride diluted in 10 ml normal saline. Thirty min later, patients in the naloxone group (group N) were given a 0.4 mg bolus, followed by a constant rate infusion of 5 micrograms.kg-1.h-1, of naloxone hydrochloride during 18 h. Patients in group P (placebo) were given normal saline instead. The degree of pain was studied with a visual analogue scale and analgesia was assessed by a clinician on a five point scale. These two parameters were obtained half an hour after the injection of morphine and 2, 4, 6 and 24 hours later. At the same time, the patients were questioned about adverse side-effects: nausea, vomiting, pruritus, dysuria, urinary retention. Respiratory depression was assessed clinically and biologically (blood gas measurements at the afore mentioned times). Heart rate, systolic and diastolic blood pressure were also measured. There was no statistically significant difference between the groups in quality and duration of analgesia. Pain reached its lowest level 4 h after the injection of morphine, returning to half its original value at the 24th h. This was also true for the incidence of nausea (11 in group N, 5 in group P), vomiting (3 in both groups), and urinary retention (6 in group P, 5 in group N).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Analgesia, Epidural; Chronic Disease; Double-Blind Method; Female; Humans; Male; Middle Aged; Morphine; Naloxone; Nausea; Neoplasms; Pain; Pain Measurement; Pruritus; Respiration Disorders; Urinary Retention; Vomiting

Persons with chronic mountain sickness (CMS) hypoventilate and are more hypoxemic than normal individuals, but the cause of the hypoventilation is unclear. Studies of 14 patients with CMS and 11 healthy age-matched control subjects residing in Lhasa, Tibet, China (3,658 m) were conducted to test the hypothesis that hypoventilation, blunted hypoxic ventilatory responsiveness (HVR), and hypoxic ventilatory depression of CMS were due to increased endogenous opioid production. Patients with CMS compared with control subjects exhibited hypoventilation (end-tidal carbon dioxide pressure [PETCO2] = 36.6 +/- 1.0 versus 31.5 +/- 0.5 mm Hg, p less than 0.05), lower tidal volume (VT = 0.54 +/- 0.02 versus 0.61 +/- 0.02 ml BTPS, p less than 0.05), blunted HVR (shape parameter A = 17 +/- 8 versus 114 +/- 22 mm Hg/L BTPS/min, p less than 0.05), and a depressant effect of ambient hypoxia on ventilation (delta PETCO2 with acute hyperoxia = -3.5 +/- 0.5 versus -1.0 +/- 0.6 mm Hg, p less than 0.05). Reduced forced expiratory volume in 1 s to vital capacity ratios (FEV1/VC) and a higher proportion of cigarette smokers in the group of patients with CMS compared with control subjects suggested that at least some patients with CMS had mild airway obstructive lung disease. Naloxone infusion (0.14 mg/kg) to six patients with CMS did not change resting VT, PETCO2, HVR, or SaO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Altitude Sickness; China; Chronic Disease; Endorphins; Humans; Hypoventilation; Hypoxia; Male; Middle Aged; Naloxone

Naloxone per se causes no pain in normal man, indicating that opioidergic antinociceptive systems are not tonically active, but this might not be the case in chronic pain conditions. The present investigation tested the hypothesis that pain in chronic headache is the result of insufficiently attenuated nociceptive impulses. Forty-seven patients suffering from chronic tension headache entered the present double-blind cross-over trial of naloxone 4 mg i.v. versus saline. Adverse effects were negligible. Patients scored headache pain on a 100 mm visual analog scale and change in headache on a 5-point verbal rating scale after 5, 15, 30, 60 and 90 min. Mean arterial blood pressure decreased 4.2 mm Hg (P less than 0.05) after naloxone compared to saline, but naloxone had no effect on headache (P = 0.96). A bimodal distribution of acute pain patients into placebo responders and non-responders has been reported, but our chronic pain patients showed a homogeneous placebo response. Review of the literature indicates that acute clinical pain and stimulation-induced analgesia in experimental pain has a naloxone-responsive component. Chronic pain does not appear to be influenced by naloxone in moderate doses.

Topics: Adult; Blood Pressure; Chronic Disease; Clinical Trials as Topic; Female; Headache; Humans; Male; Middle Aged; Muscle Contraction; Naloxone; Pain Measurement

Pain relief following stimulation of the periaqueductal gray matter (PAG) or periventricular gray matter (PVG) in man has been ascribed to stimulation-induced release of endogenous opioid substances. Forty-five patients were studied and followed for at least 1 year after placement of chronic stimulating electrodes in the PAG or PVG to determine if pain relief due to stimulation could be ascribed to an endogenous opioid mechanism. Three criteria were assessed: the development of tolerance to stimulation; the possibility of cross-tolerance to morphine; and reversibility of stimulation-induced pain relief by the opiate antagonist naloxone. Sixteen patients (35.6%) developed tolerance to stimulation, that is, they obtained progressively less effective pain relief. Twelve (44.4%) of 27 patients undergoing stimulation of the thalamic sensory relay nuclei for treatment of chronic pain (a presumably non-opioid mechanism) also developed tolerance. Morphine sulfate was administered in a blind, placebo-controlled protocol to 10 patients who had become tolerant to PAG-PVG stimulation and none showed evidence of cross-tolerance. Fifteen of 19 patients, already tolerant to morphine at the time of PAG-PVG electrode implantation, experienced excellent pain relief by stimulation, also indicating a lack of cross-tolerance. Twenty-two patients who experienced excellent pain relief from chronic PAG-PVG stimulation received intravenous naloxone in a double-blind, placebo-controlled protocol. Pain intensity as assessed by the visual analog scale was increased to the same degree by both placebo and naloxone. Eight patients showed no increase in pain intensity with either placebo or naloxone. Although tolerance to PAG-PVG stimulation developed in these patients, the frequency of tolerance was similar to that seen in patients undergoing thalamic sensory nuclear stimulation. Since the latter technique presumably relieves pain by a non-opioid mechanism, the development of tolerance to PAG-PVG stimulation does not, in itself, confirm an opioid mechanism. Cross-tolerance between PAG-PVG stimulation and morphine was not seen and cross-tolerance to PAG-PVG stimulation in patients already tolerant to morphine was rare. The pain-relieving effect of PAG-PVG stimulation was reversed to an approximately equal degree by naloxone and placebo. The authors do not believe that, in most patients, pain relief elicited by PAG-PVG stimulation depends on an endogenous opioid mechanism. It appears tha

Topics: Cerebral Aqueduct; Cerebral Ventricles; Chronic Disease; Electric Stimulation Therapy; Endorphins; Humans; Naloxone; Pain; Pain Management; Placebos; Sensory Thresholds

Chronic idiopathic gastric stasis can be responsible for unexplained dyspepsia. Because exogenous opiates inhibit gastric emptying and endogenouslike substances are present in the gastrointestinal tract, we tested the hypothesis that increased endogenous opiate activity may be responsible for chronic idiopathic gastric stasis. Eighteen patients with chronic idiopathic gastric stasis and ten healthy volunteers were studied by gastrointestinal manometry. Scintigraphic technique also was used, during which either intravenous saline or naloxone hydrochloride were infused. Manometry showed gastric hypomotility in ten patients and duodenal hyperdyskinesia in the remaining eight patients. Naloxone did not alter gastric emptying in healthy subjects or corrected gastric stasis in patients with gastric hypomotility, while it normalized gastric emptying in patients with duodenal dyskinesia. It seems that either gastroparesis or duodenal dyskinesia can promote gastric stasis and chronic dyspepsia, and endogenous opiates participate in the pathogenesis of gastric stasis in patients with duodenal dyskinesia.

Topics: Adult; Chronic Disease; Duodenum; Dyspepsia; Endorphins; Female; Gastric Emptying; Gastrointestinal Motility; Humans; Male; Manometry; Middle Aged; Naloxone; Time Factors

Topics: Abdomen; Adult; Aged; Chronic Disease; Double-Blind Method; Female; Humans; Infusions, Parenteral; Middle Aged; Naloxone; Pain

Topics: Chronic Disease; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Naloxone; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

The role of endogenous opioids on the reflex cardiovascular control of chronic uraemic patients was investigated. The opiate antagonist naloxone administered intravenously caused a significant increase in the abnormal Valsalva manoeuvre ratio in nine chronic uraemic patients, but it had no effect in six diabetic patients with normal renal function, whose response to the Valsalva manoeuvre was similar to that of chronic uraemic patients. Naloxone had no effect in eight normal subjects. The increase in the Valsalva ratio observed in uraemic patients was due to restoration of the parasympathetically mediated reflex bradycardia of the release phase of the manoeuvre. Naloxone did not modify supine and standing blood pressure and heart rate in any group. Endogenous opioids may be involved in the defective autonomic control of heart rate in uraemic patients.

Topics: Adult; Autonomic Nervous System Diseases; Blood Pressure; Chronic Disease; Diabetes Mellitus; Drug Evaluation; Heart Rate; Humans; Male; Middle Aged; Naloxone; Reflex, Abnormal; Uremia; Valsalva Maneuver

Two patients with long-standing idiopathic chronic constipation, which responded only to large daily doses of laxatives and additional suppositories and enemas, were treated with the specific opioid antagonist, naloxone, on a single-blind crossover basis. Both patients responded to naloxone treatment, with increased passage of faeces and increased wet and dry faecal weight. Although naloxone is poorly absorbed after oral administration, there was a positive response during oral as well as intravenous treatment, suggesting that the primary effect of naloxone is at specific opiate receptor sites in the myenteric plexus and other neural and endocrine cells of the intestinal wall.

Topics: Administration, Oral; Adult; Chronic Disease; Constipation; Female; Humans; Injections, Intravenous; Middle Aged; Naloxone; Placebos; Receptors, Opioid

Topics: Chronic Disease; Clinical Trials as Topic; Constipation; Double-Blind Method; Humans; Naloxone

The present study was designed to test the hypothesis that acupuncture therapy and acupuncture analgesia are both endorphin mediated. Thirty consecutive patients, all with pain at the time of treatment, were chosen. Classical acupuncture was used on seventeen patients; ear acupuncture was combined with classical Chinese acupuncture on eight patients, and ear acupuncture alone was used in five cases. No electrical stimulation of any sort was used. Pain was assessed by the patients on a visual scale of 0 to 100 before and after acupuncture therapy. Immediately following the post-acupuncture pain assessment, the patient was injected intravenously with a 1 ml. injection of 400 micrograms of Naloxone or a 1 ml. injection of 0.9% Sodium Chloride on a randomised double-blind basis. The effect on pain relief was noted immediately and after thirty minutes. No significant change in pain relief already obtained was noted after Naloxone in any patient. This does not support the hypothesis that acupuncture therapy is mediated by endorphin.

Topics: Acupuncture Therapy; Adult; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Endorphins; Female; Humans; Male; Middle Aged; Naloxone; Pain Management; Random Allocation

To determine whether the endogenous opioid peptides play a part in the pathogenesis of asthmatic morning dipping, six patients with chronic asthma with a reproducible peak flow pattern of morning dipping were investigated in a double blind, randomised, crossover study of naloxone versus placebo. Naloxone was given as a loading dose of 8 mg followed by a continuous infusion of 5.6 mg/h from midnight until 10 am on two consecutive nights. Naloxone had no significant effect on PEFR, FEV1, or FVC at 6 am. There was, however, an improvement over placebo values in all these indices between the hours of 8 am and 8 pm on the day after the first naloxone infusion in all six patients. This effect was not observed after the second naloxone infusion.

Topics: Adolescent; Adult; Asthma; Chronic Disease; Circadian Rhythm; Clinical Trials as Topic; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Naloxone; Peak Expiratory Flow Rate; Respiration; Vital Capacity

The hypothesis that the alleviation of chronic pain with hypnosis is mediated by endorphins was tested. Six patients with chronic pain secondary to peripheral nerve irritation were taught to control the pain utilizing self-hypnosis. Each subject was tested at 5-min intervals during four 1-h sessions for the amount of reduction of pain sensation and suffering associated with hypnosis while being given, in a random double-blind crossover fashion, an IV injection of either 10 mg naloxone or a saline placebo through an indwelling catheter. The patients demonstrated significant alleviation of the pain with hypnosis, but this effect was not significantly diminished in the naloxone condition. These findings contradict the hypothesis that endorphins are involved in hypnotic analgesia.

Topics: Adult; Aged; Chronic Disease; Double-Blind Method; Endorphins; Female; Humans; Hypnosis, Anesthetic; Male; Middle Aged; Naloxone; Pain; Pain Management; Time Factors

The pain relieving effect of vibratory stimulation was studied in 731 patients suffering from acute pain (135 patients) or chronic pain (596 patients). Most of the patients had previously undergone treatments of various kinds without sufficient pain relief. The effect of vibratory stimulation was assessed before, during and after stimulation using different rating scales. About 70% of the patients reported reduction of pain during vibratory stimulation. In many patients there was a clear relation between the degree of reduction of pain and the intensity of pain before the beginning of stimulation. In general, relief of pain by more than 50% during stimulation was obtained in the patients who reported light, light to moderate, or moderate pain. The patients with moderate to severe, or severe pain before stimulation generally reported a reduction of pain of 50% or less. The best pain reducing site was found to be either the area of pain or close to it, the antagonistic muscle or a trigger point near the painful area. In most patients suffering from musculoskeletal pain the best pain reducing effect was obtained when the vibratory stimulation was applied with moderate pressure (at which contact was achieved with underlying bone) at a frequency of 50-150 Hz. To obtain a maximal duration of pain relief the stimulation had to be applied for 30-45 minutes. Many of the patients experienced pain relief lasting for more than 3 hours. It may be noticed that in many patients the pain relief lasted for 12 hours or more. There was a good correlation between the degree of pain relief and its duration. In the patients who experienced a pain reduction of 50% or less the pain relief generally lasted for less than 6 hours while in the patients who experienced pain relief of more than 50% it lasted for more than 6 hours. In comparison with high or low frequency TENS, vibratory stimulation was found to be as effective and in some patients even more effective in reducing chronic musculoskeletal or orofacial pain. The effect of 20 Hz, 100 Hz and 200 Hz vibratory stimulation, high frequency TENS, low frequency TENS and "placebo" vibratory stimulation was examined in various chronic musculoskeletal pain syndromes. 82% of the patients experienced a relief of pain with any of the above mentioned methods; 47% of the patients experienced a reduction of pain with vibratory stimulation or TENS stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adolescent; Adult; Aged; Aspirin; Chronic Disease; Cryotherapy; Electric Stimulation Therapy; Female; Humans; Male; Middle Aged; Naloxone; Pain Management; Time Factors; Vibration

Naloxone produced improvement in abnormal thought content in medicated chronic schizophrenic patients, but not in drug-free patients. In contrast, drowsiness and increases in plasma prolactin concentrations were seen only in drug-free schizophrenic patients. Although growth hormone concentrations increased in drug-free and medicated schizophrenic patients, the time course was different in the two groups. Neuroleptics appear to alter naloxone's clinical and neuroendocrine effects in chronic schizophrenic patients.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Growth Hormone; Humans; Infusions, Parenteral; Male; Middle Aged; Naloxone; Prolactin; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

In a placebo-controlled, double-blind crossover study of 14 male chronic schizophrenic patients, high doses of the opiate antagonist naloxone were given intravenously. Hallucinations measured on a verbal-report scale were significantly decreased after naloxone administration. The authors suggest that this apparent action of naloxone is mediated by central opiate receptors and that it may result from an interaction between central endorphin systems and central catecholaminergic neurons.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Hallucinations; Humans; Male; Middle Aged; Naloxone; Placebos; Random Allocation; Receptors, Opioid; Schizophrenia; Schizophrenia, Paranoid

A significant number of normal and chronically anxious subjects were able to discriminate subjectively between a session in which they received naloxone and one which they received a placebo. However, affective and physiological measures did not differ significantly between the drug and placebo sessions. The weakness of the response makes it unlikely that a naloxone-responsive endogenous opioid system is substantially involved in the regulation of anxiety. An unexpected finding from the placebo session data was that, despite increased forehead muscle tension and high self-ratings of distress, chronically anxious subjects showed consistently stable sympathetic activity under resting conditions and mild stress, indicating the existence of a subgroup of generalized anxiety patients with low autonomic reactivity.

Topics: Adult; Anxiety Disorders; Chronic Disease; Emotions; Female; Humans; Male; Middle Aged; Muscle Contraction; Naloxone; Stress, Physiological; Sympathetic Nervous System

A 4-week clinical trial, including a 1-week placebo washout period, assessed the antipsychotic activity of naltrexone in 'newly admitted', actively hallucinating, chronic schizophrenics. Chronic naltrexone administration was found to benefit 2 patients and to be of no value in 3 patients. Responsive patients differed from non-responders by the presence of hallucinations despite adequate neuroleptic maintenance therapy and an appropriate response to pathological hallucinatory experience. On the basis of these findings, the possibility of a naltrexone-responsive schizophrenic subgroup was considered.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Naloxone; Naltrexone; Psychiatric Status Rating Scales; Schizophrenia

The authors conducted single- and double-blind studies of the responses of 7 chronic male schizophrenic patients to 10 mg of naloxone. BPRS ratings were made before and 6 hours after the injection; ACTH blood levels were determined before and 1 1/2 and 6 hours after injection. Statistically significant improvement of psychotic behavior occurred after 6 hours. The greatest improvement occurred in the patient who showed the most pronounced diurnal variation of ACTH levels, and there was no improvement in the patient who had no diurnal changes. Prolactin plasma levels following endorphin injections were apparently dose-dependent and peaked at approximately 30 minutes. The mean half-life of elimination of exogenous beta-endorphin was between 12 and 35 minutes. The authors theorize that positive and negative behavioral responses to naloxone depend--as possibly do many placebo responses in general--on the relative stress produced by experimental or therapeutic interventions.

Topics: Adrenocorticotropic Hormone; Adult; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Endorphins; Half-Life; Humans; Male; Middle Aged; Naloxone; Prolactin; Psychiatric Status Rating Scales; Schizophrenia; Stress, Psychological

Endogenous opiate-like peptides (endorphins) are putative neuroregulators located throughout the mammalian brainstem. There is some evidence for their role in pain, stress, and affect. We report that the opiate antagonist, naloxone, alters some schizophrenic symptoms. In a double-blind, cross-over study, naloxone produced decreases in auditory hallucinations in some schizophrenic patients. This finding supports the hypothesis that the endorphins may play a roll in modulating hallucinations in a highly selected subgroup of chronically hallucinating schizophrenic patients.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Endorphins; Hallucinations; Humans; Male; Naloxone; Schizophrenia; Schizophrenia, Paranoid; Time Factors

Fourteen schizophrenic patients and five patients with affective disorders were given naloxone (0.4 to 10 milligrams) or placebo intravenously in a double-blind fashion. Physicians' ratings of hallucinations, mannerisms and posturing, conceptual disorganization, psychosis, and mood did not change significantly. A single item, unusual thought content, improved significantly on the naloxone day compared to the placebo day. There was no improvement in mood in affectively ill patients rated either by themselves or by physicians. Naloxone did not markedly improve any patient studied, which suggests that the acute blockade of opiate receptors is not associated with global improvement in psychotic symptomatology.

Topics: Adolescent; Adult; Affective Symptoms; Behavior; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Hallucinations; Humans; Male; Middle Aged; Naloxone; Schizophrenia

42 outpatients with chronic diarrhoea of varying origin received individually adapted doses (2--12 mg) of loperamide for a median time of 543 days (range 140--1,159 days). In most cases, the mean daily stool frequency dropped significantly and stool consistency improved clearly; the beneficial effects of the drug were maintained over the entire treatment period. Also, patients with diarrhoea of organic origin tended to react more favourably to loperamide than patients with functional diarrhoea. No drug-related changes in laboratory parameters could be detected and clinical side effects were virtually nil. No morphine-like effect of loperamide could be evidence by means of the pupil diameter changes after naloxone administration.

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Diarrhea; Double-Blind Method; Drug Evaluation; Female; Humans; Isotonic Solutions; Loperamide; Male; Middle Aged; Naloxone; Piperidines; Pupil; Sodium Chloride; Time Factors

The specific narcotic antagonist naloxone (0.4 milligram) was given intravenously to seven chronic schizophrenics who reported that they had very frequent auditory hallucinations. Saline solution was used as a placebo. The coded study did not reveal any effect of naloxone on hallucinations or on global psychopathology.

Topics: Adult; Chronic Disease; Female; Hallucinations; Humans; Male; Middle Aged; Naloxone; Schizophrenia

Topics: Adult; Aged; Amides; Antidiarrheals; Chlorobenzenes; Chronic Disease; Clinical Trials as Topic; Colitis, Ulcerative; Colonic Diseases, Functional; Crohn Disease; Diarrhea; Drug Evaluation; Female; Gastrointestinal Agents; Humans; Isonipecotic Acids; Male; Middle Aged; Naloxone; Nitriles; Piperidines; Placebos; Reflex, Pupillary

Preventing and treating opioid dependence and withdrawal is a major clinical challenge, and the underlying mechanisms of opioid dependence and withdrawal remain elusive. We hypothesized that prolonged morphine exposure or chronic inflammation-induced μ-opioid receptor activity serves as a severe stress that elicits neuronal alterations and recapitulates events during development. Here, we report that Wnt signaling, which is important in developmental processes of the nervous system, plays a critical role in withdrawal symptoms from opioid receptor activation in mice. Repeated exposures of morphine or peripheral inflammation produced by intraplantar injection of complete Freund's adjuvant significantly increase the expression of Wnt5b in the primary sensory neurons in dorsal root ganglion (DRG). Accumulated Wnt5b in DRG neurons quickly transmits to the spinal cord dorsal horn (DH) after naloxone treatment. In the DH, Wnt5b, acts through the atypical Wnt-Ryk receptor and alternative Wnt-YAP/TAZ signaling pathways, contributing to the naloxone-precipitated opioid withdrawal-like behavioral symptoms and hyperalgesia. Inhibition of Wnt synthesis and blockage of Wnt signaling pathways greatly suppress the behavioral and neurochemical alterations after naloxone-precipitated withdrawal. These findings reveal a critical mechanism underlying naloxone-precipitated opioid withdrawal, suggesting that targeting Wnt5b synthesis in DRG neurons and Wnt signaling in DH may be an effective approach for prevention and treatment of opioid withdrawal syndromes, as well as the transition from acute to chronic pain.

Topics: Analgesics, Opioid; Animals; Cells, Cultured; Chronic Disease; Inflammation; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Posterior Horn Cells; Receptors, Opioid; Substance Withdrawal Syndrome; Wnt Proteins; Wnt Signaling Pathway

The present study explores the pain attenuating effect of perampanel, AMPA receptor antagonist, in chronic constriction injury-induced neuropathic pain. Chronic Constriction Injury was performed by putting four loose ligatures around the sciatic nerve. Pain was assessed by determining mechanical hyperalgesia, cold allodynia and heat hyperalgesia on 7th and 14th day post surgery. Perampanel (3mg and 6mg/kg, p.o.) was administered 30min before pain assessment test on 14th day post-surgery. CCI led to significant development of pain and peak symptoms were observed on 14th day. Perampanel significantly attenuated CCI-induced mechanical hyperalgesia, cold allodynia and heat hyperalgesia, at different time intervals 30, 60, 90, 120min, with more substantial effect observed at dose of 6mg/kgNaloxone was administered in CCI subjected rats before perampanel treatment to explore the potential role of opioids in anti-nociceptive effects of perampanel. Naloxone decreased the pain attenuating effects of perampanel significantly, indicating a critical role of opioid system in anti-nociceptive potential of perampanel. Perampanel has pain attenuating potential in CCI-induced neuropathic pain, which may be due to partly mediated through the opioid system.

Topics: Animals; Chronic Disease; Constriction; Disease Models, Animal; Female; Hyperalgesia; Male; Motor Activity; Naloxone; Neuralgia; Nitriles; Pyridones; Rats, Wistar

Stigmasterol is a common sterol found in plants, but the anti-nociceptive effect of this compound and its mechanism of action are not fully explored. Thus, in the present study, the anti-nociceptive effect of stigmasterol was investigated in acute and chronic models of pain and its mechanism of action. We used adult male albino Swiss mice (25-35 g) to observe the anti-nociceptive effect of stigmasterol in acetic-acid writhing test or in complete Freund's adjuvant injection, surgical incision in hind paw, or partial sciatic nerve ligation. Moreover, we investigate the involvement of opioid receptors (naloxone, 2 mg/kg, intraperitoneally) in stigmasterol anti-nociceptive effect and stigmasterol action on acetylcholinesterase activity. Some possible adverse effects caused by stigmasterol were also investigated. Stigmasterol (0.3-3 mg/kg, orally) exhibited an anti-nociceptive effect on acetic-acid-induced writhing test. Furthermore, it markedly attenuated the mechanical allodynia caused by surgical incision (after acute treatment with stigmasterol, preventive and curative effects were observed) and partial sciatic nerve ligation (after acute treatment with stigmasterol) and complete Freund's adjuvant (after acute or repeated treatment with stigmasterol). The anti-nociceptive effect of stigmasterol was not reversed by naloxone. Moreover, stigmasterol did not alter in vitro acetylcholinesterase activity in spinal cord or brain samples. Also, stigmasterol did not cause gastric ulcers or alter the gastrointestinal transit of mice. Taken together, these results support the potential anti-nociceptive effect of stigmasterol in different models of pain.

Topics: Acetic Acid; Acetylcholinesterase; Acute Disease; Analgesics; Animals; Brain; Chronic Disease; Freund's Adjuvant; Gastrointestinal Transit; Hyperalgesia; Male; Mice; Naloxone; Narcotic Antagonists; Pain; Sciatic Nerve; Spinal Cord; Stigmasterol; Stomach

Psychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways.. Mouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca. Supernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca. Stress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.

Topics: Adult; Aged; Animals; beta-Endorphin; Biopsy; Chronic Disease; Colitis; Colon; Cytokines; Ganglia, Spinal; Humans; Mice; Mice, Inbred C57BL; Middle Aged; Naloxone; Nociceptors; Patch-Clamp Techniques; Signal Transduction; Stress, Psychological

This work aimed to determine the chemical fingerprint of hydroethanolic extract of leaves of Caryocar coriaceum (HELCC) and the gastroprotective activity. The chemical fingerprint of HELCC was analyzed by HPLC-DAD, to quantify total phenols and flavonoids were carried out by Folin-Ciocalteu reagent and aluminum chloride assay, while in vitro antioxidant activity was evaluated by the DPPH method. The methods used to determine pharmacological activity were: gastroprotective screening test in classical models of induced acute and chronic gastric lesions and physical barrier test. Further assays were performed to demonstrate the involvement of NO, prostaglandins, ATP-dependent potassium channels, TRPV, noradrenergic α2 receptors, histamines, and opioids. The DPPH method demonstrated the antioxidant activity of the extract, in vitro, explained by the presence of polyphenols and flavonoids. Oral administration of the extract, previously dissolved in deionized water, at a dose of 100 mg/kg decreased the lesions induced by indomethacin, acidified ethanol, ethanol and acetic acid by 75.0, 72.8, 69.4 and 86.2% respectively. It was demonstrated that opioid receptors, α

Topics: Animals; Antioxidants; Capsaicin; Chromatography, High Pressure Liquid; Chronic Disease; Disease Models, Animal; Ericales; Ethanol; Female; Flavonoids; Gastrointestinal Motility; Glyburide; Histamine; Indomethacin; Male; Mice; Mucus; Naloxone; NG-Nitroarginine Methyl Ester; Phenols; Phytotherapy; Plant Extracts; Plant Leaves; Protective Agents; Stomach Ulcer; Water; Yohimbine

Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Dysfunction of DA homeostasis leading to high or low DA levels is causally linked to addiction. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. Using quantitative real-time polymerase chain reaction, immunofluorescence and Western blotting, we studied the effects of single morphine administration, morphine dependence and withdrawal on the DA markers DA transporters (DAT), vesicular monoamine transporters (VMAT2) and DA 2 receptor subtype (DRD2), DA 1 receptor subtype as well as tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and/or nucleus accumbens (NAc). In addition, Nurr1 and Pitx3 expression was also measured. Present data showed a high degree of colocalization of Nurr1 and Pitx3 with TH(+) neurons in the VTA. We found that the increased Nurr1 and/or Pitx3 levels during morphine dependence and in morphine-withdrawn rats were associated to an increase of DAT, VMAT2 and DRD2. Altogether, present data indicate that morphine dependence and withdrawal induced consistent alterations of most of the DA markers, which was correlated with transcription factors involved in the maintenance of DA neurons in drug-reward pathways, suggesting that Nurr1 and Pitx3 regulation might be associated with controlling adaptation to chronic morphine and to morphine withdrawal-induced alterations of DA neurons activity in the mesolimbic pathway.

Topics: Acute Disease; Animals; Biomarkers; Chronic Disease; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drug Implants; Homeodomain Proteins; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Nuclear Receptor Subfamily 4, Group A, Member 2; Nucleus Accumbens; Rats, Wistar; Receptors, Dopamine D2; RNA, Messenger; Substance Withdrawal Syndrome; Transcription Factors; Ventral Tegmental Area; Vesicular Monoamine Transport Proteins

Topics: Anticonvulsants; Biological Products; Biosimilar Pharmaceuticals; Canada; Centers for Medicare and Medicaid Services, U.S.; Chronic Disease; Commerce; Cost Savings; Deductibles and Coinsurance; Drug Approval; Drug Costs; Drugs, Generic; Economics, Pharmaceutical; Epinephrine; Financial Audit; Humans; Imatinib Mesylate; Insurance Benefits; Insurance Coverage; Insurance, Pharmaceutical Services; Legislation, Drug; Medication Adherence; Medication Therapy Management; Naloxone; Pharmacies; State Government; Therapeutic Equivalency; United States; United States Food and Drug Administration

There is high comorbidity between depression and addiction. Features of addiction relevant to depression have been studied extensively, but less is known about features of depression relevant to addiction. Here, we have studied the effects of chronic mild stress (CMS), a valid animal model of depression, on measures of physical and psychological dependence resulting from subchronic treatment of rats with three drugs of abuse that act through disparate neurobiological mechanisms: morphine, nicotine and diazepam. In animals not treated subchronically with drugs of abuse, CMS increased the withdrawal-like effects of the opiate antagonist naloxone, but not those of the nicotinic antagonist mecamylamine or the benzodiazepine antagonist flumazenil. In animals treated subchronically with drugs of abuse, CMS exacerbated, precipitated and conditioned withdrawal effects associated with all three antagonists. CMS also potentiated withdrawal-induced and cue-induced place aversions associated with all three antagonists. All of the effects of CMS were reversed by chronic treatment with the specific serotonin reuptake inhibitor citalopram. These results suggest that treatment of comorbid depression, although not a primary treatment for addiction, may facilitate other treatments for addiction, by decreasing the severity of withdrawal symptoms and the likelihood of relapse.

Topics: Animals; Chronic Disease; Citalopram; Depressive Disorder; Diazepam; Disease Models, Animal; Flumazenil; GABA Modulators; Male; Mecamylamine; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Rats, Wistar; Selective Serotonin Reuptake Inhibitors; Stress, Psychological; Substance Withdrawal Syndrome; Substance-Related Disorders

Opioid-induced constipation (OIC) is a severe, persisting side-effect of opioid therapy. The Bowel Function Index (BFI(a), numerical analogue scale 0 - 100), calculated as the mean of three variables (ease of defaecation, feeling of incomplete bowel evacuation, and personal judgement of constipation) was developed to evaluate bowel function in opioid-treated patients with pain. This clinician-administered tool allows easy measurement of OIC from the patient's perspective. The purpose of this investigation was to define a reference range reflecting BFI values in non-constipated chronic pain patients who were recruited into a cross-sectional survey and asked for their perceptions of constipation. The BFI scores were assessed and compared with those of patients with confirmed OIC obtained from two previously published trials. Results were analysed and a reference range of BFI values of 0 - 28.8, into which 95% of non-constipated chronic pain patients fell, was defined. This permits discrimination between chronic pain patients with, or without, constipation.

Topics: Analgesics, Opioid; Chronic Disease; Constipation; Cross-Sectional Studies; Defecation; Female; Germany; Humans; Male; Middle Aged; Naloxone; Oxycodone; Pain; Quality of Life; Reference Values; Research Design; Surveys and Questionnaires

Over the past twenty years, neuroscience has changed our understanding of placebo analgesia. Often perceived by researchers as a response bias adding noise to the assessment of efficacy, in the patients' view, it is associated with charlatanism. The origin of the word, qualifying a patient's response to "please" the doctor, did not help its rightful appreciation. However, today the placebo analgesia is considered as a psychobiological phenomenon. Thanks to pharmacological manipulations and the development of functional brain imaging, the neural circuitry involved in this effect as well as the role of endorphins and dopamine have been identified. This article describes our current knowledge about this fascinating phenomenon: a psychological modulation can lead to a biological effect.

Topics: Aged; Analgesia; Chronic Disease; Dopamine; Endorphins; Female; Humans; Naloxone; Narcotic Antagonists; Neurosciences; Osteoarthritis, Knee; Pain; Placebo Effect; Placebos; Prefrontal Cortex; Treatment Outcome

Topics: Administration, Oral; Analgesics, Opioid; Chronic Disease; Constipation; Drug Combinations; Evidence-Based Medicine; Humans; Naloxone; Narcotic Antagonists; Oxycodone; Pain; Quality of Life; Switzerland; Treatment Outcome

The implication of inducible nitric-oxide synthase (iNOS) on peripheral tolerance to morphine was evaluated in wild-type (WT) and iNOS knockout mice. Chronic inflammation was induced by subplantar (s.p.) injection of Complete Freund's Adjuvant (CFA), and morphine tolerance by subcutaneous implantation of a 75 mg morphine-pellet. Withdrawal was assessed after the intraperitoneal injection of 2 mg/kg naloxone. Antinociception was assessed (Randall-Selitto test) 5 min after a fixed dose of s.p. morphine (16 microg). In the absence of inflammation, s.p. morphine did not induce antinociception, while during CFA-inflammation produced 47.4 +/- 0.8 and 38.8 +/- 2.7% inhibitions respectively, in each genotype (P < 0.05). In morphine-tolerant mice with CFA-inflammation, no antinociception could be elicited in WT mice (2.4 +/- 0.3% inhibition); however, iNOS knockout mice showed significant antinociception (33.1 +/- 0.9%) (P < 0.001). Thus, iNOS gene deletion partially prevented tolerance to the peripheral effects of morphine, and significantly attenuated withdrawal-induced hyperactivity.

Topics: Animals; Arthritis, Experimental; Chronic Disease; Disease Models, Animal; Drug Tolerance; Gene Deletion; Inflammation; Inflammation Mediators; Mice; Mice, Inbred C57BL; Mice, Knockout; Morphine; Naloxone; Nitric Oxide Synthase Type II; Pain Measurement; Substance Withdrawal Syndrome

This case report presents data regarding endogenous opioid analgesia in a healthy female subject prior to developing chronic pain, and again 4 and 13 months following onset of chronic daily back pain. At each assessment period, the subject underwent identical protocols involving two sessions one week apart with randomized double-blind crossover administration of saline placebo and naloxone, an opioid antagonist. Each session included a 5-min anger recall interview, followed by finger pressure and ischemic acute pain tasks. Increases in acute pain ratings induced by opioid blockade were interpreted as reflecting endogenous opioid analgesia. When the subject was healthy and pain-free, naloxone produced a mean overall 16% decrease in pain ratings relative to placebo. However, 4 months after onset of chronic pain, a mean naloxone-induced increase of 22% in pain ratings over placebo was observed, consistent with presence of endogenous opioid analgesia. The mean magnitude of this opioid blockade effect for the finger pressure task exceeded the 99% confidence interval for the healthy control population based on a previous study using a similar opioid blockade protocol [4]. At 13-month follow-up, naloxone produced a mean 45% decrease in acute pain ratings compared to placebo, arguing against presence of endogenous opioid analgesia. Although results must be interpreted cautiously, findings are consistent with the hypothesis that chronic pain may initially be associated with upregulation of endogenous opioid analgesic systems which then may become dysfunctional over time.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Analgesics, Opioid; Back Pain; Chronic Disease; Female; Follow-Up Studies; Humans; Middle Aged; Naloxone; Narcotic Antagonists; Pain Measurement

Recently, opioid receptors have been shown to be expressed on group III and IV afferents, which comprise the sensory arm of the exercise pressor reflex. Although the stimulation of opioid receptors in the central nervous system has been shown to attenuate the exercise pressor reflex, the effect on the reflex of their stimulation in the periphery is unknown. We therefore tested the hypothesis that the activation of peripheral mu-opioid receptors attenuates the exercise pressor reflex. The pressor responses to static contraction were compared before and after the injection of the mu-opioid receptor agonist [d-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO; 1 microg) into the abdominal aorta of decerebrated rats in which one femoral artery had been occluded 72 h previously (n = 10) and in control rats whose femoral arteries were freely perfused (n = 8). DAMGO attenuated the peak pressor response to contraction in rats whose femoral arteries had been occluded (before: increase of 34 + or - 3 mmHg and after: increase of 22 + or - 2 mmHg, P = 0.008); the inhibitory effect of DAMGO was prevented by the injection of naloxone (100 microg) into the abdominal aorta (before: increase of 29 + or - 5 mmHg and after: increase of 29 + or - 5 mmHg, P = 0.646, n = 7). An intravenous injection of DAMGO (1 microg, n = 6) had no effect on the peak pressor response to contraction in both groups of rats. DAMGO had no effect on the peak pressor response to contraction in rats whose femoral arteries were freely perfused (before: Delta 23 + or - 4 mmHg, after: Delta 23 + or - 3 mmHg, n = 6) but appeared to have a small effect on topography of the response. DAMGO had no effect on the peak pressor response to tendon stretch in both groups of rats (both P > 0.05). We conclude that the stimulation of peripheral mu-opioid receptors attenuates the exercise pressor reflex in rats whose femoral arteries have been ligated for 72 h.

Topics: Animals; Arterial Occlusive Diseases; Baroreflex; Chronic Disease; Constriction, Pathologic; Disease Models, Animal; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Femoral Artery; Hindlimb; Injections, Intra-Arterial; Injections, Intravenous; Ligation; Male; Muscle Contraction; Muscle, Skeletal; Naloxone; Narcotic Antagonists; Neurons, Afferent; Physical Exertion; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Time Factors

The transdermal 7-day buprenorphine matrix patch provides a constant and user-friendly pain management when chronic musculoskeletal pain requires opioids. This analysis of clinical routine data evaluated the benefit of this treatment for patients previously receiving oral long-term treatment with weak opioids alone. Data of 310 patients previously treated with tramadol or tildate/naloxone and part of a multicentre observational study with 3295 patients were analyzed. In 89.7% of the 310 patients oral treatment with weak opioids was replaced by the 7-day buprenorphine patch due to insufficient analgesia. During treatment with the 7-day buprenorphine patch there was a clinically significant decrease of the mean pain intensity at rest during the day from 5.7 to 2.9, on physical effort during the day from 7.3 to 3.8 and at night from 5.2 to 2.3 (11-point NRS scale, p < or = 0.001). In addition, quality of life aspects such as mobility, self-reliance and quality of sleep improved, which are relevant for individual patient satisfaction with pain management. For patients with previous long-term tramadol or tilidate/naloxone treatment the switch to the 7-day buprenorphine matrix patch proved to be effective and safe for the management of chronic pain. The user-friendly 7-day application interval contributes to improving compliance and a reducing exposure to tablets.

Topics: Activities of Daily Living; Administration, Cutaneous; Aged; Aged, 80 and over; Analgesics, Opioid; Buprenorphine; Chronic Disease; Drug Substitution; Female; Germany; Humans; Long-Term Care; Male; Middle Aged; Naloxone; Pain; Pain Measurement; Prospective Studies; Quality of Life; Tilidine; Tramadol

Withdrawal of opioid drugs leads to a cluster of unpleasant symptoms in dependent subjects. These symptoms are stimulatory in nature and oppose the acute, inhibitory effects of opiates. The conventional theory that explains the opioid withdrawal syndrome assumes that chronic usage of opioid drugs activates compensatory mechanisms whose stimulatory effects are revealed upon elimination of the inhibitory opioid drug from the body. Based on previous studies that show a dose-dependent dual activity of opiates, including pain perception, we present here an alternative explanation to the phenomenon of withdrawal-induced hyperalgesia. According to this explanation, the residual low concentration of the drug that remains after cessation of its administration elicits the stimulatory withdrawal hyperalgesia. The goal of the present study was to test this hypothesis. In the present study we rendered mice dependent on morphine by a daily administration of the drug. Cessation of morphine application elicited withdrawal hyperalgesia that was completely blocked by a high dose of the opiate antagonist naloxone (100 mg/kg). Similarly, naloxone (2 mg/kg)-induced withdrawal hyperalgesia was also blocked by 100 mg/kg of naloxone. The blockage of withdrawal hyperalgesia by naloxone suggested the involvement of opioid receptors in the phenomenon and indicated that withdrawal hyperalgesia is a direct effect of a residual, low concentration of morphine. Acute experiments that show morphine- and naloxone-induced hyperalgesia further verified our hypothesis. Our findings offer a novel, alternative approach to opiate detoxifications that may prevent withdrawal symptoms by a complete blockage of the opioid receptors using a high dose of the opioid antagonist.

Topics: Animals; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Hyperalgesia; Male; Mice; Mice, Inbred ICR; Morphine; Naloxone; Narcotic Antagonists; Nociceptors; Receptors, Opioid; Severity of Illness Index; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Administration, Topical; Aged; Analgesics, Opioid; Buprenorphine; Cholestasis; Chronic Disease; Drug Combinations; Female; Humans; Injections, Intravenous; Naloxone; Narcotic Antagonists; Neoplasms; Pain; Pain Measurement; Palliative Care; Pruritus; Treatment Outcome

Naloxone is an opioid receptor antagonist with effects on the EEG and behavior in animals and humans and has been used clinically in drug-abuse treatment. The goal of this work in the rat is to determine whether treatment with naloxone during the suckling period would influence the propagation of cortical spreading depression (CSD), both in weaned young and adult animals. From the 7th to the 28th postnatal day, male rat pups were treated daily with a single subcutaneous injection of either 10mg/kg/d naloxone (n=21 rats) or equivalent volume (10ml/kg) of saline (n=16). In both treatment conditions, when the pups were 30-40 days- (young groups; 9 Naloxone- and 10 saline-treated rats), or 90-120-days old (adult groups; 12 Naloxone- and 6 saline-treated rats), a 4h CSD recording session was performed with electrodes at two points at a fixed distance apart on the parietal cortical surface. CSD propagation velocity was calculated based on the time spent for a CSD-wave to pass between the electrodes. In both young- and adult groups, naloxone-treated animals displayed lower CSD velocities (P<0.05) than the corresponding saline injected animals. Our results demonstrate, for the first time, that chronic neonatal exposure of rats to the opioid antagonist naloxone results in an impairing propagation of the CSD that is long lasting, suggesting the existence of one or more opioid-mediated processes influencing CSD.

Topics: Action Potentials; Aging; Animals; Animals, Newborn; Animals, Suckling; Brain; Chronic Disease; Cortical Spreading Depression; Disease Models, Animal; Drug Administration Schedule; Male; Naloxone; Narcotic Antagonists; Opioid Peptides; Opioid-Related Disorders; Rats; Rats, Wistar; Time

Opioid and excitatory amino acid receptors contribute to morphine dependence, but there are no studies of their role in heroin dependence. Thus, mice injected with acute or chronic heroin doses in the present study were pretreated with one of the following selective antagonists: 7-benzylidenenaltrexone (BNTX), naltriben (NTB), nor-binaltorphimine (nor-BNI; delta1, delta2, and kappa opioid receptors, respectively), MK-801, or LY293558 (NMDA and AMPA excitatory amino acid receptors, respectively). Naloxone-precipitated withdrawal jumping frequency, shown here to be a reliable index of heroin dependence magnitude, was reduced by BNTX or NTB in mice injected with both acute and chronic heroin doses. In contrast, nor-BNI did not alter jumping frequencies in mice injected with an acute heroin dose but significantly increased them in mice receiving chronic heroin injections. Continuous MK-801 or LY293558 infusion, but not injection, reduced jumping frequencies during withdrawal from acute heroin treatment. Their delivery by injection was nonetheless effective against chronic heroin dependence, suggesting mechanisms not simply attributable to NMDA or AMPA blockade. These data indicate that whereas delta1, delta2, NMDA, and AMPA receptors enable acute and chronic heroin dependence, kappa receptor activity limits the dependence liability of chronic heroin. With the exception of delta1 receptors, the apparent role of these receptors to heroin dependence is consistent with their contribution to morphine dependence, indicating that there is substantial physiological commonality underlying dependence to both heroin and morphine. The ability of kappa receptor blockade to differentially alter acute and chronic dependence supports previous assertions from studies with other opioids that acute and chronic opioid dependence are, at least in part, mechanistically distinct. Elucidating the substrates contributing to heroin dependence, and identifying their similarities and differences with those of other opioids such as morphine, may yield effective treatment strategies to the problem of heroin dependency.

Topics: Acute Disease; Animals; Behavior, Animal; Benzylidene Compounds; Chronic Disease; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Heroin Dependence; Male; Mice; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Substance Withdrawal Syndrome; Time Factors

Heroin and morphine exposure can cause physical dependence, with symptoms manifesting during their withdrawal. Inter-individual differences in symptom frequency during morphine withdrawal are a common finding that, in rodents, is demonstrably attributable to genotype. However, it is not known whether inter-individual differences characterize heroin withdrawal, and whether such variation can be similarly influenced by genotype. Therefore, we injected mice of ten inbred strains with acute and chronic heroin doses and compared their jumping frequencies, a common index of withdrawal magnitude, during naloxone-precipitated withdrawal. The data revealed significant strain frequency differences (range after acute and chronic heroin injection: 0-104 and 0-142 jumps, respectively) and substantial heritability (h(2)=0.94 to 0.96), indicating that genetic variance is associated with heroin withdrawal. The rank order of strain sensitivity for acute and chronic heroin withdrawal jumping, and for the current heroin and previous morphine strain data, were significantly correlated (r=0.75-0.94), indicating their genetic and, ultimately, physiological commonality. These data suggest that the genetic liability to heroin dependence remains constant across a period of heroin intake, and that heroin and morphine dependence may benefit from common treatment strategies.

Topics: Acute Disease; Animals; Chronic Disease; Genetic Variation; Genotype; Heroin Dependence; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; Species Specificity; Substance Withdrawal Syndrome

Tramadol (1RS, 2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol) is an atypical centrally acting analgesic agent with weak opioid receptor affinity that, like some antidepressants, enhances the extraneuronal concentrations of the monoamine neurotransmitters, noradrenaline and serotonin, by interfering with their re-uptake and release mechanisms.. The present study was undertaken to evaluate the potential role of 5-HT(1A) receptors and opioids receptors in the analgesic effect of tramadol in neuropathic pain. With this aim, the effect of either a selective 5-HT(1A) receptor antagonist (WAY-100635, N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT(1A) receptor agonist (8-OH-DPAT, 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) or an opioid receptor antagonist (naloxone; naloxone hydrochloride dihydrate) was investigated in combination with tramadol by means of the cold-plate test in the chronic constriction injury model in rats.. The results showed that WAY-100635 (0.8 mg/kg) significantly enhanced the antiallodynic effect of non-effective doses of tramadol (5-10 mg/kg). In contrast, 8-OH-DPAT (0.5 mg/kg) counteracted the antiallodynic effect of an effective dose of tramadol (22 mg/kg). Naloxone (0.5 mg/kg) partially counteracted the antiallodynic effect of tramadol (22 mg/kg).. These findings suggest the involvement of opioid and 5-HT(1A) receptors in the antinociceptive effect of tramadol and support the idea that the combination of tramadol with compounds having 5-HT(1A) antagonist properties could be a new strategy to improve tramadol-induced analgesia in neuropathic pain.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Analgesics, Opioid; Animals; Chronic Disease; Disease Models, Animal; Drug Interactions; Male; Naloxone; Narcotic Antagonists; Pain; Pain Threshold; Piperazines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptors, Opioid; Sciatic Nerve; Sciatic Neuropathy; Serotonin 5-HT1 Receptor Agonists; Tramadol

Topics: Chronic Disease; Clinical Trials as Topic; Constipation; Delayed-Action Preparations; Drug Combinations; Humans; Naloxone; Narcotics; Oxycodone; Pain

Low-dose naloxone-precipitated withdrawal hyperalgesia is a reliable indicator of physical dependence after chronic morphine treatment. A remarkably similar long-lasting (>3-4 h) hyperalgesia is evoked by injection of a low dose of naloxone (10 microg/kg, s.c.) in naïve mice after acute pretreatment with the glycolipid, GM1 ganglioside (1 mg/kg) (measured by warm-water-immersion tail-flick assays). GM1 treatment markedly increases the efficacy of excitatory Gs-coupled opioid receptor signaling in nociceptive neurons. Co-treatment with an ultra-low-dose (0.1 ng/kg, s.c.) of the broad-spectrum opioid receptor antagonist, naltrexone or the selective kappa opioid receptor antagonist, nor-binaltorphimine, blocks naloxone-evoked hyperalgesia in GM1-pretreated naïve mice and unmasks prominent, long-lasting (>4 h) inhibitory opioid receptor-mediated analgesia. This unmasked analgesia can be rapidly blocked by injection after 1-2 h of a high dose of naltrexone (10 mg/kg) or nor-binaltorphimine (0.1 mg/kg). Because no exogenous opioid is administered to GM1-treated mice, we suggest that naloxone may evoke hyperalgesia by inducing release of endogenous bimodally acting opioid agonists from neurons in nociceptive networks by antagonizing putative presynaptic inhibitory opioid autoreceptors that "gate" the release of endogenous opioids. In the absence of exogenous opioids, the specific pharmacological manipulations utilized in our tail-flick assays on GM1-treated mice provide a novel bioassay to detect the release of endogenous bimodally acting (excitatory/inhibitory) opioid agonists. Because mu excitatory opioid receptor signaling is blocked by ultra-low doses of naloxone, the higher doses of naloxone that evoke hyperalgesia in GM1-treated mice cannot be mediated by activation of mu opioid receptors. Co-treatment with ultra-low-dose naltrexone or nor-binaltorphimine may selectively block signaling by endogenous GM1-sensitized excitatory kappa opioid receptors, unmasking inhibitory kappa opioid receptor signaling, and converting endogenous opioid receptor-mediated hyperalgesia to analgesia. Co-treatment with kelatorphan stabilizes putative endogenous opioid peptide agonists released by naloxone in GM1-treated mice, so that analgesia is evoked rather than hyperalgesia. Acute treatment of chronic morphine-dependent mice with ultra-low-dose naltrexone (0.1 ng/kg) results in remarkably similar rapid blocking of naloxone (10 microg/kg)-precipitated withdrawal hyperalgesia

Topics: Analgesics, Opioid; Animals; Chronic Disease; Dipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; G(M1) Ganglioside; Hyperalgesia; Male; Mice; Morphine; Morphine Dependence; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Opioid Peptides; Receptors, Opioid, kappa; Substance Withdrawal Syndrome

It has been proposed, with some supporting evidence, that development of opiate tolerance and dependence requires protein synthesis. However, a quantitative, biologically based model within which to analyse and support the data has been lacking. Utilizing such a framework or model, we recently compared the time course of onset of opiate dependence in laboratory animals, with the mathematical time course of general changes in protein levels. Not only did the time course of onset of dependence parallel the time course of increasing levels of a protein, but also the half-life of the putative protein required by the model was very similar to those of many brain proteins. In this study, we have more extensively tested the model by producing and examining a much more detailed and surprisingly complex time course of the onset of dependence. Applying the protein synthesis time course model to the data suggested the presence of two distinct components of dependence, an early transient component and a later long-lasting component. These components appear to correspond to acute and chronic dependence, respectively. The protein synthesis hypothesis more readily applies to the chronic dependence portion. Because consideration of the model can generate components that correspond to accepted and well-known components of dependence, both the utility of the model as well as the hypothesis that opiate dependence at least partially requires protein synthesis are supported. It is also possible that individual components of the withdrawal syndrome have individual and unique rate limiting mechanisms. In any case, time course analysis may be helpful in revealing underlying mechanisms of change.

Topics: Acute Disease; Animals; Chronic Disease; Dose-Response Relationship, Drug; Male; Models, Biological; Naloxone; Opioid-Related Disorders; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Opioids are commonly used in the treatment of moderate to severe pain. However, their chronic use is limited by analgesic tolerance and physical dependence. Few studies have examined how chronic pain affects the development of tolerance or dependence, and essentially no studies have looked at the role of both genetics and pain together. For these studies we used 12 strains of inbred mice. Groups of mice from each strain were tested at baseline for morphine analgesic sensitivity, mechanical nociceptive threshold, and thermal nociceptive threshold. Mice were then given morphine in a 4-day escalating morphine administration paradigm followed by reassessment of the morphine dose-response relationship. Finally, physical dependence was measured by administering naloxone. Parallel groups of mice underwent hind paw injection of complete Freund's adjuvant (CFA) to induce chronic hind paw inflammation 7 days prior to the beginning of testing. The data showed that CFA treatment tended to lower baseline ED(50) values for morphine and enhanced the degree of analgesic tolerance observed after 4 days of morphine treatment. In addition, the degree of jumping behavior indicative of physical dependence was often altered if mice had been treated with CFA. The influence of background strain was substantial for all traits measured. In silico haplotypic mapping of the tolerance and physical dependence data demonstrated that CFA pretreatment altered the pattern of the predicted associations and greatly reduced their statistical significance. We conclude that chronic inflammatory pain and genetics interact to modulate the analgesic potency of morphine, tolerance, and physical dependence.

Topics: Analgesics, Opioid; Animals; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Freund's Adjuvant; Genetic Predisposition to Disease; Genotype; Inflammation Mediators; Male; Mice; Mice, Inbred AKR; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred MRL lpr; Morphine; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Pain Threshold; Species Specificity

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Chronic Disease; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pain; Tilidine; Time Factors

The present study was aimed at evaluating chronic stress models in mice with special attention to morphine treatment. We hypothesized that repeated periods of drug withdrawal induce chronic stress. To verify this hypothesis, mice were made dependent on morphine and then subjected to several types of repeated withdrawal. Body weight reduction, thymus involution, adrenal gland enlargement and activation of the hypothalamo-pituitary-adrenal axis were used as signs of chronic stress. The changes were compared to those induced by 'laboratory' models of chronic stress (2 weeks of repeated restraint or rat exposure) and to a disease model of streptozotocin-induced diabetes mellitus (STZ-DM). Mice were made dependent using increasing doses of morphine three times a day for 3 days (10-20-40 mg/kg s.c.). Thereafter, withdrawal was induced either spontaneously (morphine 40 mg/kg injected at 24- or 72-hour time intervals for 2 weeks) or repeatedly precipitated by naloxone (10 mg/kg s.c.) injected daily 3 h after morphine. The results show that repeated periods of spontaneous drug withdrawal (24 or 72 h) in morphine-dependent mice represent a mild stress load. Repeated withdrawal precipitated by naloxone induced clear chronic stress-like changes. Changes observed in the naloxone-precipitated withdrawal model were even more pronounced than those found in laboratory models, namely repeated restraint or exposure to the rat. The most severe chronic stress state developed in mice during untreated STZ-DM. Thus, naloxone-precipitated withdrawal in mice seems to be an appropriate model of chronic stress.

Topics: Animals; Chronic Disease; Diabetes Mellitus, Experimental; Disease Models, Animal; Male; Mice; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Restraint, Physical; Social Environment; Stress, Physiological; Substance Withdrawal Syndrome

Topics: Aged; Analgesics, Opioid; Arthralgia; Chronic Disease; Clinical Trials as Topic; Delayed-Action Preparations; Drug Combinations; Humans; Middle Aged; Musculoskeletal Diseases; Naloxone; Osteoarthritis; Pain Measurement; Patient Satisfaction; Tilidine; Treatment Outcome

Itch is a major symptom of skin disease and is poorly understood, in part due to the lack of adequate small animal models. We show, using iontophoresis of histamine and capsaicin, that it is possible to induce scratching behaviour in both guinea pig and mouse. Use of iontophoresis may obviate the problems of induction of pain as well as itch when injection is used. The behavioural response to capsaicin, however, differs from that seen with histamine, raising the possibility that the use of scratch counts as a method of measuring itch severity needs to be set in the context of other responses. Naloxone partly inhibits scratching in mouse and guinea pig due to histamine. We also show that contact sensitization with 2-4 dinitrochlorobenzene (DNCB) can be used as a simple assay for chronic itch allowing study of scratching over at least a 15-h period. The characteristics of scratching (but not the time course) induced with DNCB are similar to those seen with histamine.

Topics: Acute Disease; Animals; Capsaicin; Chronic Disease; Dinitrochlorobenzene; Disease Models, Animal; Female; Guinea Pigs; Haptens; Histamine; Iontophoresis; Male; Mice; Mice, Inbred BALB C; Naloxone; Pruritus

Physical dependence is a widely known consequence of morphine intake. Although commonly associated with prolonged or repeated morphine administration, withdrawal symptoms can be elicited even after a single prior morphine exposure. What remains contentious is the extent to which physical dependence following acute and chronic morphine treatment is mediated by common physiological substrates and, accordingly, represent distinct syndromes. The genetic relationship between acute and chronic morphine dependence was thus presently studied by comparing mice of 11 inbred strains (129P3, A, AKR, BALB/c, C3H/He, C57BL/6, CBA, DBA/2, LP, SJL, and SWR) for naloxone-precipitated withdrawal jumping responses using three subcutaneous morphine administration paradigms: acute (single injection) or chronic (three daily morphine injections for 4 days) injection, or chronic infusion (7 days via implanted osmotic minipumps). Although there were differences in the magnitude of withdrawal jumping between the three different morphine administration paradigms, large and significant strain differences were observed for each. In addition, the same strains were unusually sensitive or, conversely, altogether refractory to withdrawal jumping across all morphine treatment conditions. Overall, strain jumping means between acute and chronic dependence paradigms displayed a high degree of genetic correlation (r=0.87-0.95). The significant correlation between chronic morphine injection and continuous morphine infusion discounts the possible confounding effect of contextual learning and spontaneous withdrawal between chronic injections on the assessment of naloxone-precipitated withdrawal. Substantial heritability was also observed for acute and both paradigms of chronic dependence, with estimates ranging from h(2)=0.53 to 0.70. The present demonstration of a strong genetic correlation between physical dependence to morphine following acute and chronic treatment implies that genes associated with variable sensitivity in the two traits are the same, and is suggestive of shared physiological substrates. The data also demonstrate that the differential genetic liability to morphine physical dependence begins with, and is predicted by, the first morphine exposure.

Topics: Acute Disease; Analgesics, Opioid; Animals; Chronic Disease; Female; Male; Mice; Mice, Inbred A; Mice, Inbred AKR; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Inbred DBA; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Species Specificity; Substance Withdrawal Syndrome

Self-mutilation or self-injurious behaviour is a well known behavioural disorder in humans. The proposition that this behaviour in animals is a response to chronic pain of peripheral nerve injury has been met with controversy. In the present study a pharmacological model, which produces no sensory or motor loss was used to study how autotomy is related to pain. In a group of rats autotomy was induced by amphetamine in phenoxybenzamine and reserpine treated animals. The pain tests, both phasic and tonic were then performed. The results of this study showed that a total analgesia was produced in both phasic and tonic pain tests, in animals that exhibited autotomy. Injection of naloxone in these animals prevented autotomy. A correlation between autotomy and no pain is suggested in this pharmacological model of autotomy.

Topics: Adrenergic alpha-Antagonists; Adrenergic Uptake Inhibitors; Amphetamine; Analgesia; Animals; Behavior, Animal; Central Nervous System Stimulants; Chronic Disease; Denervation; Disease Models, Animal; Male; Naloxone; Narcotic Antagonists; Pain; Pain Measurement; Phenoxybenzamine; Rats; Rats, Wistar; Reserpine; Self Mutilation

The influence of both acute and chronic restraint stress on the rewarding properties of morphine (1, 2 or 3 mg/kg i.p.) and the aversive effects of naloxone (0.5 mg/kg i.p. x3 or 1.0 mg/kg i.p.) or bremazocine (0.4 mg/kg i.p.) was investigated. An acute (2 h) but not chronic restraint (2 h daily for 7 days) enhanced the morphine place preference, and elicited a place aversion with a subthreshold dose of bremazocine. This enhancing effect on the reinforcing properties induced by the drugs was prevented by either R(+)-SCH-23390 hydrochloride (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H3-benzazepine, 30 microg/kg i.p.) or (+/-)-sulpiride (60 mg/kg i.p.), 10-20 min prior to the stress session. Naltrexone pretreatment (1 mg/kg i.p.) abolished the stress effect on morphine place preference but not that on bremazocine aversion. Instead, nor-BNI (30 microg/3 microl i.c.v.) abolished the stress's effects on bremazocine aversion, but did not modify those on morphine preference. These results show that: (1) acute stress enhanced the morphine and bremazocine conditioned reinforcing effects meanwhile chronic stress did not modify them; (2) the stimulation of D(1) and D(2) dopamine receptors is necessary for the development of restraint stress-induced sensitization to the conditioned reinforcing effects of drugs; and (3) the stimulation mu/delta- and kappa-opioid receptors seems to be differentially involved.

Topics: Acute Disease; Animals; Behavior, Animal; Benzomorphans; Chronic Disease; Conditioning, Operant; Injections, Intraventricular; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Opioid, kappa; Receptors, Opioid, mu; Stress, Psychological

Previous research has revealed an antinociceptive (analgesic) effect of interleukin-2 (IL-2) in central and peripheral nervous systems. Unfortunately IL-2 is very short-lived in vivo, so it is impractical to apply IL-2 for analgesia in clinic. This study was performed to evaluate the effect of intrathecal delivery of human IL-2 gene on rat chronic neuropathic pain induced by chronic constriction injury of the sciatic nerve. Human IL-2 cDNA was cloned into pcDNA3 containing a cytomegalovirus promoter. The paw-withdrawal latency induced by radiant heat was used to measure the pain threshold. The results showed that recombinant human IL-2 had a dose-dependent antinociceptive effect, but that this only lasted for 10-25 min. The pcDNA3-IL-2 or pcDNA3-IL-2/lipofectamine complex in contrast also showed dose-dependent antinociceptive effects, but these reached a peak at day 2-3 and were maintained for up to 6 days. Liposome-mediated pcDNA3-IL-2 produced a more powerful antinociceptive effect than pcDNA3-IL-2 alone. The paw-withdrawal latencies were not affected by control treatments such as vehicle, lipofectamine, pcDNA3, or pcDNA3-lipofectamine. In the experimental groups, human IL-2 mRNA was detected by reverse transcription-polymerase chain reaction in the lumbar spinal pia mater, dorsal root ganglion, sciatic nerve, and spinal dorsal horn, but not in gastrocnemius muscle. The expressed IL-2 profile detected by western blot coincided with its mRNA profile except it was present in the spinal dorsal horn at a higher level. Furthermore, human IL-2 assayed by enzyme-linked immunosorbent assay in cerebrospinal fluid could still be detected at day 6, but lower than day 3. The antinociceptive effect of pcDNA3-IL-2 could be blocked by naloxone, showing some relationship of the antinociceptive effect produced by IL-2 gene to the opioid receptors. It is hoped that the new delivery approach of a single intrathecal injection of the IL-2 gene described here may be of some practical use as a part of a gene therapy for treating neuropathic pain.

Topics: Animals; Cation Exchange Resins; Chronic Disease; COS Cells; Disease Models, Animal; DNA, Complementary; Dose-Response Relationship, Drug; Genetic Therapy; Humans; Injections, Spinal; Interleukin-2; Ligation; Lipids; Liposomes; Male; Naloxone; Narcotic Antagonists; Organ Specificity; Pain; Pain Management; Pain Measurement; Rats; Rats, Sprague-Dawley; Recombinant Proteins; RNA, Messenger; Sciatic Neuropathy; Signal Transduction; Tissue Distribution; Transfection

The study examined the validity of oral fentanyl self-administration (FSA) as a measure of the chronic nociceptive pain that develops in rats with adjuvant arthritis independently of acute noxious challenges. Arthritic rats self-administered more of a 0.008 mg/ml fentanyl solution (up to 3.4 g/rat per day) than non-arthritic controls (0.5 g/rat per day) and did so with a biphasic time course that reached peak during weeks 3 and 4 after inoculation with Mycobacterium butyricum. The time course paralleled both the disease process and the chronic pain. Continuous infusion of dexamethasone during weeks 3 and 4 via subcutaneous osmotic pumps at 0.0025-0.04 mg/rat per day disrupted the arthritic disease and decreased FSA to a level (i.e. by 65%) similar to that observed in non-arthritic rats. Continuous naloxone (2.5 mg/rat per day) decreased FSA (by 55%) in arthritic but not in non-arthritic animals. Continuous, subcutaneous infusion of fentanyl also decreased arthritic FSA in a manner that varied with dose at 0.04-0.16 mg/rat per day doses, but leveled off at 47% of controls with 0.31 mg/rat per day. The effects of continuous fentanyl on arthritic FSA occurred only with those doses and dose-dependent dynamics with which fentanyl also induced dependence in non-arthritic rats. The findings indicate that pain, rather than the rewarding or dependence-inducing action of fentanyl mediates FSA in arthritic rats. Paralleling patient-controlled analgesic drug intake, FSA offers a specific measure allowing the dynamic effects of neurobiological agents to be studied in this unique animal model of persistent nociceptive pain.

Topics: Analgesics, Opioid; Animals; Arthritis; Behavior, Animal; Chronic Disease; Fentanyl; Male; Naloxone; Narcotic Antagonists; Narcotics; Nociceptors; Pain; Pain Measurement; Palliative Care; Rats; Rats, Inbred Lew; Reference Values; Self Administration; Substance-Related Disorders; Time Factors

Previous research has shown an increase in hypothalamo-pituitary-adrenal axis activity following naloxone administration to morphine-dependent rats. In the present study, we investigated the adaptive changes in the noradrenaline (NA) and dopamine (DA) systems in the hypothalamic paraventricular nucleus (PVN) during morphine dependence and withdrawal. Additionally, we examined the possible change in 3',5'-cyclic adenosine monophosphate (cAMP) levels in that nucleus under the same conditions. Rats were made dependent on morphine by morphine or placebo (naïve) pellet implantation for 7 days. On day 8, rat groups received an acute injection of saline or naloxone (1 mg/kg subcutaneously) and were decapitated 30 min later. NA and DA content as well as their metabolite production in the PVN were estimated by HPLC/ED. Both plasma corticosterone levels and cAMP concentration in the PVN were measured by RIA. Naloxone administration to morphine-dependent rats (withdrawal) induced a pronounced increase in the production of both the NA metabolite MHPG and the DA metabolite DOPAC and an enhanced NA and DA turnover. Furthermore, an increase in corticosterone secretion was observed in parallel to the changes in catecholamine turnover. However, no alterations in cAMP levels were seen during morphine withdrawal. These results raise the possibility that catecholaminergic afferents to the PVN could play a significant role in the alterations of PVN functions and consequently in the pituitary-adrenal response during morphine abstinence syndrome. These data provide further support for the idea of adaptive changes in catecholaminergic neurons projecting to the PVN during chronic morphine exposure.

Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Behavior, Animal; Body Weight; Chronic Disease; Corticosterone; Cyclic AMP; Dopamine; Male; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Narcotics; Norepinephrine; Paraventricular Hypothalamic Nucleus; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

The objective of this study was to examine the antinociceptive effects of peripherally restricted kappa-opioid receptor agonists (ORAs) in a rat model of inflammatory bowel disease produced by intracolonic instillation of trinitrobenzine sulfonic acid (TNBS). Antinociceptive effects of mu-(morphine) and kappa-ORAs (EMD 61,753 and ICI 204,488) were evaluated in a behavioral model of visceral nociception. The effects of these agonists and a delta-ORA (SNC 80) on responses of pelvic nerve afferent fibers innervating the colon were also tested. In the behavioral study, systemic injections of morphine and both kappa-ORAs dose-dependently inhibited the visceromotor response to colorectal distension in rats with uninflamed or inflamed colons. The inhibitory effects of kappa-ORAs, but not morphine, were significantly greater in rats with colons inflamed 4 days previously by TNBS. A mu-receptor-selective dose (30 microg/kg) of naloxone methiodide (NLXM) blocked the inhibitory effect of morphine, but not of EMD 61,753. In the single-fiber study, neither morphine nor the delta-ORA SNC 80 attenuated the responses of pelvic nerve afferent fibers, whereas kappa-ORAs dose-dependently inhibited responses of pelvic nerve afferent fibers with significantly greater potency in the inflamed colon. Pretreatment with a non-opioid receptor-selective dose (2 mg/kg) of NLXM produced a rightward shift in the dose-response function of EMD 61,753. The greater potency of kappa-ORAs in the TNBS-inflamed condition suggests a peripheral upregulation of kappa-opioid receptors in colonic inflammation.

Topics: Acetamides; Action Potentials; Analgesics, Opioid; Animals; Benzamides; Chronic Disease; Colitis; Colon; Electrophysiology; Male; Morphine; Naloxone; Narcotic Antagonists; Nerve Fibers; Neurons, Afferent; Pain Measurement; Piperazines; Pressure; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Rectum; Trinitrobenzenesulfonic Acid

The present study examined the influence of an early chronic variable stress procedure with or without concurrent naloxone administration at different doses (1, 2 or 3 mg/kg, i.p.) on stress (restraint)-induced dopamine release in the frontal cortex in vivo. A higher increase in cortical dopamine release in response to a subsequent restraint event was observed in chronically stressed rats as compared with those without chronic stress exposure. Naloxone pretreatment normalized this sensitized response only at the higher dose (3 mg/kg, i.p.). The present results indicate that cortical dopamine response to a novel and uncontrollable stressor sensitizes after exposure to a chronic variable stress procedure and that an endogenous opiate mechanism, presumably activated during chronic stress, may be involved in the development of such a sensitization process.

Topics: Animals; Chronic Disease; Dopamine; Frontal Lobe; Male; Microdialysis; Naloxone; Narcotic Antagonists; Opioid Peptides; Rats; Rats, Wistar; Restraint, Physical; Stress, Physiological

The aim of our study was to investigate the effect of intracerebroventricular (i.c.v.) administration of very low doses of opioid antagonists on the pain threshold, arterial blood pressure and body temperature of spontaneously hypertensive rats (SHR) with chronic pain. We found that low doses of i.c.v. administered naloxone hydrochloride (0.3 microg) or naloxone methiodide (0.4 microg) produce paradoxical hypoalgesia. Similar results were not observed following i.c.v. administration of nor-binaltorphimine (0.6 microg). A paradoxical increase in the severity of hypertension followed i.c.v. opioid antagonist administration. This suggests an involvement of the opioid system in the mechanisms of blood pressure control. The paradoxical results obtained both for pain threshold and blood pressure after low doses of some opioid antagonists seem to confirm the role played by opioid autoreceptors in these effects. Existence of autoreceptors is suggested. Results obtained following i.c.v. administration of nor-binaltorphimine also suggest a role for the kappa autoreceptor (OP2) in the regulatory mechanisms of thermoregulation.

Topics: Analgesia; Animals; Arteries; Blood Pressure; Body Temperature; Body Weight; Brain; Chronic Disease; Hypertension; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Pain Threshold; Quaternary Ammonium Compounds; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Baclofen (beta-p-chlorophenyl-GABA) has been used in humans to treat spasticity, as well as trigeminal neuralgia. Since GABA (gamma-aminobutyric acid) has been implicated in inhibitory and analgesic effects in the nervous system, it was of interest to study the effect of baclofen in experimental neuropathic pain. With this purpose, experiments were carried out in 17 neuropathic rats with constrictive sciatic injury, as described by Bennet and Xie (1988), taking as pain parameters scratching behaviour and the latency to the thermal nociceptive stimulus. The results showed that baclofen induces, in a dose-dependent manner, significant decrease (p < 0.05) of scratching behaviour and significant increase (p < 0.05) of the latency to the nociceptive thermal stimulus. The absence of antagonism of naloxone suggested a non-participation of an opioid-mediated mechanism in this analgesic effect of baclofen on experimental neuropathic pain.

Topics: Animals; Baclofen; Behavior, Animal; Chronic Disease; GABA Agonists; Male; Naloxone; Narcotic Antagonists; Pain; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Sciatic Nerve

To assess the role of beta-EP in the physiological and pathophysiological process of respiratory regulation in chronic hypoxic rats.. The chronic hypoxic rat model was established by intravenous injections of papain 6 times, once a week. The concentration of beta-endorphin in medulla, pons, hypothalamus, central gray and plasma of chronic hypoxic rats were measured by radioimmunoassay. All animals were pretreated with sodium pentobartital (35 mg/kg) before experiment. 102 rats were randomly divided into three groups. Group 1 (n = 36). The respiratory rate (RR) and tidal volume (VT) were measured after intravenous injection of naloxone (NLX, 2 mg/kg), beta-EP (40 micrograms/kg, 160 micrograms/kg) or normal saline, Group 2 (n = 48). By the intracerebroventricular administration of NLX and beta-EP to the models, RR, VT and PaCO2 were observed after microinjection 5, 15, 30, 45, 60 min. Group 3 (n = 18). The respiratory effects of beta-EP after directly into the nucleus tractus solitari of the anaesthetised rats were investigated.. The beta-EP contents in medulla, pons, hypothalamus, central gray and plasma of chronic hypoxic rats were significantly increased compared with control subjects (P < 0.01). It suggested that the pathophysiology of chronic hypoxic process infleuced the contents of beta-EP in the CNS and plasma in rats. Intracerebroventricular microinjection of beta-EP in normal rats, resulted in a significant decrease in RR (P < 0.05). No significant difference in RR and VT was observved after intravenous injection of naloxone (2 mg/kg) and beta-EP (40 micrograms/kg, 160 micrograms/kg) in treatment group compared with the control group (P > 0.05), Intracerebroventricular microinjection of NLX in chronic hypoxic rats, resulted in a marked increase in RR (P < 0.05) and central hypercapnic-sensitivity (t = 2.76, P < 0.05), Intracerebroventriculalr microinjection of beta-EP in chronic hypoxic models, resulted in severe respiratory depression after injection 15, 30, 45, 60 min (RR t = 3.41, 6.54, 6.97, 7.87, P < 0.01; VT t = 3.07, 7.27, 6.14, 6.08).. These results indicate the beta-endorphin may be involved in central respiratory control of chronic hypoxic rats.

Topics: Animals; beta-Endorphin; Chronic Disease; Disease Models, Animal; Hypoxia; Male; Naloxone; Narcotic Antagonists; Oxygen; Rats; Rats, Sprague-Dawley; Respiration

The development of tolerance and dependence to morphine injected onto the spinal cord was examined in a model of chronic pain following spinal cord injury in rats. Intrathecal morphine completely relieved the marked pain-like response of these rats to innocuous mechanical stimuli. The analgesic effect of morphine injected twice daily was, however, diminished within a few days. Tolerance to the antinociceptive effect of morphine assessed with the tail flick test also developed similarly in rats with chronic pain and in normal controls. Both groups exhibited similar signs of naloxone-precipitated withdrawal after 3 weeks of morphine treatment. The results suggest that the presence of chronic pain-like behavior did not prevent the development of morphine tolerance and dependence, even when morphine was used to treat the chronic pain itself.

Topics: Animals; Behavior, Animal; Chronic Disease; Drug Tolerance; Female; Hyperesthesia; Injections, Spinal; Morphine; Naloxone; Narcotic Antagonists; Pain; Rats; Rats, Sprague-Dawley; Reference Values; Spinal Cord Injuries; Substance Withdrawal Syndrome; Substance-Related Disorders

In rodents, noncompetitive and competitive NMDA receptor antagonists have been shown to attenuate and, in some cases, reverse tolerance to the analgesic effects of morphine. However, the ability of these same excitatory amino acid (EAA) receptor antagonists to modulate morphine dependence is controversial, and very little is known about the role of AMPA receptors in morphine dependence. LY293558, a novel, systemically active, competitive AMPA receptor antagonist and the NMDA receptor antagonists, MK-801 and/or LY235959, were evaluated in tolerant or dependent CD-1 mice. In mice rendered tolerant by morphine injection or pellet implantation, continuous s.c. infusion of LY293558 (60 mg/kg per 24 h) or MK-801 (1 mg/kg per 24 h) attenuated the development of tolerance. Neither LY293558 nor MK-801 produced analgesia or altered the ED50 value of morphine. Continuous s.c. infusion of LY293558 (60 mg/kg per 24 h), MK-801 (1 mg/kg per 24 h) or LY235959 (12 mg/kg per 24 h) attenuated the development of acute (3 h) morphine dependence (i.e., decreased naloxone-precipitated withdrawal jumping). In contrast, continuous s.c. infusion of LY293558 (60 mg/kg per 24 h) or LY235959 (12 mg/kg per 24 h) did not significantly attenuate the development of chronic dependence produced by morphine pellet implantation. These data indicate that the development of morphine tolerance is more sensitive to modulation by EAA receptor antagonists than is the development of morphine dependence as assessed by naloxone-precipitated withdrawal jumping.

Topics: Acute Disease; Animals; Chronic Disease; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Tolerance; Excitatory Amino Acid Antagonists; Infusions, Parenteral; Isoquinolines; Male; Mice; Mice, Inbred Strains; Morphine Dependence; Naloxone; Narcotic Antagonists; Receptors, AMPA; Tetrazoles

1. Currently available pharmacological therapies treat arthritis inadequately. We have previously found that the kappa (kappa)-opioid, U-50,488H (trans-(+/-)- 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]- benzene-acetamide methane sulphonate), possesses anti-arthritic effects. In light of the finding that opioid receptors in the periphery are upregulated during inflammation, kappa-opioids may represent a novel therapy for arthritis. The primary aim and unique feature of the present study is to investigate whether opioids exert their anti-arthritic effects in the periphery. Thus, the dose-effect relationship of a kappa-opioid agonist, U-50,488H was compared after both local and distant administration. Further, we tested whether the anti-arthritic effects of this drug are stereospecific and receptor-mediated by use of opioid antagonists. 2. Using an adjuvant model of arthritis in male Lewis rats, arthritis was judged by oedema, radiography and histological changes in the contralateral ankle of the hind limb. Treatment with (+/-)-U-50,488H for 3 days during disease onset and 3 days during established disease significantly attenuated arthritis, but the effects of (+/-)-U-50,488H on radiology and histology varied according to treatment time. Administration of (+/-)-U-50,488H during disease onset had a more marked effect on radiography, suggesting that treatment with that drug should be started early to prevent progressive joint destruction. Further, it was found that (+/-)-U-50,488H, administered for 3 days during the disease onset, either by direct subcutaneous injection into the inflamed paw or at a more distant site into the back of the neck, dose-dependently attenuated arthritic damage as measured by an index which pooled all three variables. More importantly however, (+/-)-U-50,488H was approximately fourfold more potent as an 'anti-arthritic' agent after local compared to distant subcutaneous injection (ED50; local vs distant: 5.8 +/- 1.6 vs 19.5 +/- 0.8 mg kg-1). 3. Equivalent doses of the (-)-enantiomer (20 mg kg-1day-1) and the racemate (+/-) of U-50,488H (40 mg kg-1day-1), elicited a similar attenuation of arthritic parameters while the (+/-)-enantiomer exacerbated arthritis, suggesting that the anti-arthritic activity lies solely with the (-)-enantiomer. 4. Both the peripherally selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266 ((-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan), were

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Arthritis, Experimental; Benzomorphans; Chronic Disease; Dose-Response Relationship, Drug; Hindlimb; Male; Mycobacterium; Naloxone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Inbred Lew; Receptors, Opioid, kappa; Stereoisomerism; Time Factors

The aim of our study was to evaluate the effects of endogenous opioids on the secretion of atrial natriuretic factor (ANF) in moderate chronic heart failure (HF).. We evaluated the effects of i.v. volume load (NaCl 0.9% at 0.25 ml/Kg/min for 60 minutes) on heart rate (HR), on mean arterial pressure (MAP) and on the plasma levels of beta-endorphin (beta-end), met-enkephalin (Met-enk), dynorphin (Dyn), atrial natriuretic factor (ANF) and noradrenaline (NA) in 10 patients (age 58 +/- 9) with HF in NYHA class II (group I) and in 8 healthy control subjects (age 54 +/- 10) group II). The volume load was repeated after at least three days during infusion of naloxone (2 micrograms/Kg/min), evaluating the above mentioned hemodynamic and hormonal parameters.. The acute volume expansion caused an increase in ANF concentration (from 51.7 +/- 19.7 to 67.4 +/- 36.9 pg/ml; p < 0.05) and in beta-end (from 11.9 +/- 5.3 to 16.6 +/- 7.5 fmol/ml; p < 0.05), In group I. In group II an isolated increase in ANF was observed (from 14.1 +/- 7.8 to 21.9 +/- 7.9 pg/ml; p < 0.02). No significant changes were detected for HR, MAP, Dyn, Met-enk and NA. In group I the percent increase of ANF is less than in group II (30 vs 55%; p < 0.05). The volume load infused during naloxone infusion caused a significant increase in HR (from 73 +/- 6 to 78 +/- 9 bpm; p < 0.05) and in NA (from 311 +/- 123 to 415 +/- 142 pg/ml; p < 0.05) In group I. In group II, an increase in ANF was detected (from 13.8 +/- 6.0 to 23.6 +/- 5.0 pg/ml; p < 0.01).. Our data suggest that in moderate HF beta-end stimulates the secretion of ANF and inhibits the activity of the sympatho-adrenergic system during acute volume expansion.

Topics: Adult; Aged; Analysis of Variance; Atrial Natriuretic Factor; beta-Endorphin; Chronic Disease; Data Interpretation, Statistical; Dynorphins; Enkephalin, Methionine; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Norepinephrine; Plasma Volume; Receptors, Adrenergic; Sodium Chloride; Sympathetic Nervous System

Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A(2-13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1-17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1-17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.

Topics: Animals; Chronic Disease; Dizocilpine Maleate; Dynorphins; Excitatory Amino Acid Antagonists; Injections, Spinal; Male; Naloxone; Narcotic Antagonists; Pain; Peptide Fragments; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sensory Thresholds

Acute resistive loading of the airway has been shown to activate the endogenous opioid system, with subsequent depression of ventilation. The present investigation was designed to assess the effect of chronic airway loading on ventilation and CO2 sensitivity, and to determine whether the endogenous opioid system contributes to long-term modulation of ventilatory control in this setting. A flow-resistive ventilatory load was imposed in 2-mo-old rats by surgical implantation of a circumferential tracheal band that approximately tripled tracheal resistance. Respiration and CO2 sensitivity were serially and noninvasively assessed by barometric plethysmography over a period of 21 wk. Ventilatory output was assessed as minute inspiratory effort, which was defined as the product of plethysmograph signal amplitude, inspiratory time, and respiratory rate (RR). CO2 sensitivity was calculated as the percent change in minute inspiratory effort from room air to CO2 exposure. The effect of naloxone administration on these parameters was also determine. Arterial blood gases demonstrated hypercapnia with maintenance of normoxia in loaded rats; these findings persisted for the duration of the study. Two days after surgery, rats with tracheal obstruction demonstrated a lower RR than controls during room air breathing and during CO2 stimulation. CO2 sensitivity was significantly depressed in obstructed animals at this time. Escape from suppression of RR and CO2 sensitivity was evident by 14 to 21 d after obstruction; however, suppression of these parameters reappeared and was maintained from 56 to 147 d after obstruction. Naloxone augmented minute inspiratory effort during CO2 stimulation at 2 d after obstruction but not thereafter; naloxone had no effect in control rats. These data indicate that chronic airway loading suppresses RR and CO2 sensitivity in a triphasic manner. The early suppression is partially reversible by naloxone; late-appearing suppression is unaffected by naloxone and is presumably mediated by mechanisms that do not involve endogenous opioids.

Topics: Airway Obstruction; Airway Resistance; Animals; Carbon Dioxide; Chronic Disease; Disease Models, Animal; Eating; Hypercapnia; Inhalation; Male; Naloxone; Opioid Peptides; Oxygen; Oxygen Consumption; Plethysmography; Pulmonary Ventilation; Rats; Rats, Sprague-Dawley; Respiration; Tracheal Diseases

The present study assesses the influence of different restraint schedules on behavioral parameters determined by a conflict test, namely the light-dark transitions (LDT) as well as the opiate modulation on the behavioral consequences induced by chronic restraint. Finally, another group of animals that received naloxone (NAL) and/or chronic stress was either exposed to a single foot shock session or administered a single dose of the beta-carboline FG 7142 (N'-methyl-beta-carboline-3-carboxamide) immediately prior to the LDT test. We observed that a single restraint session (2 h) induced a decrease of LDT and time spent in the lit box, while chronic restraint (2 h per day for up to 7 days) induced a significant increase in both parameters. However, this increasing effect was blocked by a NAL administration (2 mg/kg IP) prior to each of the seven restraint events. A single foot shock or FG administration produced a clear anxiogenic response, an effect that was absent in animals previously submitted to chronic stress. In addition, NAL pretreatment abolished the chronic stress-induced attenuating effect on the behavioral suppression induced after either foot shock or FG administration. Therefore, these findings demonstrate that a previous history of chronic stress, leading to adaptation, induced an anxiolytic-like effect, and attenuated the behavioral suppression produced by acute stressors. There seems to be an endogenous opiate mechanism involved in the behavioral influence induced by chronic stress.

Topics: Adaptation, Psychological; Analysis of Variance; Animals; Anxiety Disorders; Chronic Disease; Conflict, Psychological; Male; Naloxone; Rats; Rats, Wistar; Restraint, Physical; Stress, Physiological

The adjuvant arthritic rat model has been utilized for the study of chronic pain, as polyarthritic rats present a variety of symptoms similar to those seen in human chronic pain conditions. In particular, hyperventilatory responses are notable in both and may more accurately reflect basal ongoing pain than do evoked noxious stimuli. To assess whether adrenal medullary transplants in the spinal subarachnoid space can alleviate basal arthritic pain, respiratory parameters were determined using whole body plesthmography in polyarthritic rats. Arthritis was induced by inoculation with an intradermal injection of complete Freund's adjuvant. Steady-state ventilation was monitored at weekly intervals in arthritic animals with adrenal medullary or control striated muscle transplants. Results revealed that adjuvant arthritis produced significant hyperventilation in animals with control transplants, as indicated by increased tidal volumes and minute ventilation, which paralleled the progression of the inflammatory process. In contrast, this hyperventilation was eliminated by adrenal medullary transplants. A role for catecholamines and opioid peptides released from the transplants was suggested by the reversal of these effects with phentolamine and naloxone. In addition, the retardation in weight gain normally observed in polyarthritic animals was markedly attenuated by adrenal medullary, but not control transplants. These findings indicate that adrenal medullary transplants in the spinal subarachnoid space can alleviate basal chronic pain as assessed in adjuvant arthritis.

Topics: Adrenal Medulla; Adrenergic alpha-Antagonists; Animals; Arthritis, Experimental; Catecholamines; Chronic Disease; Hyperventilation; Naloxone; Narcotic Antagonists; Opioid Peptides; Pain; Pain Management; Phentolamine; Rats; Rats, Sprague-Dawley; Respiratory Mechanics; Subarachnoid Space; Weight Gain

The behaviors displayed in a forced swim test were investigated in rats previously exposed to a chronic variable stress treatment or chronic administration of morphine. In addition, to further explore the participation of an endogenous opiate mechanism in these behavioral effects, naloxone was either administered during the chronic treatment (prior to each stress or morphine exposure) or immediately prior to the forced swim test. Animals were submitted daily to a different stressor for 1 week or injected with morphine (10 mg/kg, IP) for 6 days, whereas controls were unmanipulated except for the injection process. On the day following the last stressor, control and stressed animals were administered saline or naloxone (2 mg/kg, IP) 15 min prior to the forced swim test. Morphine treated animals were similarly tested on the third day following the last morphine injection. In a separate group of rats, naloxone (2 mg/kg, IP) was administered daily 10 min prior to each stressor of the chronic stress regime or each daily morphine injection. A significant increase in the time spent in immobility was observed in stressed animals as well as in rats chronically treated with morphine. In both groups, this potentiated immobility was attenuated by naloxone pretreatment prior to the forced swim test or when given before each daily stressor or morphine injection. In addition, the concurrent exposure to stress or morphine along with naloxone administration enhanced struggling in the first 5 min of the forced swim test.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Chronic Disease; Male; Morphine; Motor Activity; Naloxone; Rats; Rats, Sprague-Dawley; Stress, Psychological; Swimming

We have recently developed a rat model of chronic pain states after spinal cord injury. Thus, after severe, but incomplete, ischemic spinal cord injury, some rats chronically exhibited responses indicative of pain to innocuous mechanical stimuli (allodynia) in the rostral dermatomes involving the injured spinal segments. These responses have some characteristics in common with chronic central pain in patients with spinal cord injury. We now report that systemic CI988, a specific antagonist of the cholecystokinin (CCK) type B receptor, effectively relieved the allodynia-like symptom, an effect that was reversed by the opioid receptor antagonist naloxone. Furthermore, in rats which did not develop the allodynia-like symptom after spinal cord lesion, systemic naloxone induced typical allodynia. In contrast, naloxone failed to produce allodynia in normal animals. It is thus suggested that the abnormal sensory processing initiated by spinal cord ischemic lesion is under tonic opioidergic control and dysfunction of this control by the upregulated endogenous CCK system is responsible for the development of painful sensations in these rats.

Topics: Animals; Anti-Anxiety Agents; Behavior, Animal; Cholecystokinin; Chronic Disease; Diazepam; Endorphins; Female; Indoles; Meglumine; Naloxone; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Spinal Cord Injuries; Vocalization, Animal

In chronic experiments with rats during the exercises on a treadmill the ECG was registered and duration of the development of exhaustion was determined under control and under acute (1 mg/kg intraperitoneally 1 hour before the experiment) or chronic (1 mg/kg intraperitoneally, twice a day during 5 days) treatment with the opioid receptor antagonist naloxone. Chronic but not acute naloxone action resulted in increase of the fatiguability: the time of achievement of exhaustion decreased by 55.3% (P < 0.05). In this case the exhaustion developed at lower degree of heart rate than in control. Comparison of data obtained with the results of chronic treatment with the opioid antagonist permits to conclude that the chronic blockade increases the fatiguability to a great extent than chronic activation of opioid system. Possible mechanisms causing this difference are under discussion.

Topics: Acute Disease; Animals; Chronic Disease; Electrocardiography; Fatigue; Heart Rate; Male; Naloxone; Physical Exertion; Rats; Receptors, Opioid; Running

The effect of the presence of either chronic or acute clinical pain on pain threshold and on the nociceptive flexion reflex (RIII) threshold was studied. The experimental pain sensation and the flexion reflex were evoked by trains of short electrical pulses. It was hypothesized that both kinds of clinical pain would be able to induce 'diffuse noxious inhibitory controls' (DNIC) and thereby raise the 2 experimental thresholds. Patients with chronic low back pain, patients with postoperative pain from oral surgery, and pain-free subjects were tested in 3 conditions: during baseline, after i.v. administration of a placebo, and after i.v. administration of naloxone. In comparison with 2 pain-free control groups, the 2 pain groups had a significantly higher pain threshold in all conditions. However, the RIII threshold was not significantly elevated in chronic or acute pain patients compared to controls. Naloxone had no effect on the RIII or pain threshold in any of the groups. It is concluded that the increased pain threshold which is frequently found in chronic pain patients, and which could be confirmed in the present study, does not result from a DNIC effect. The adaptation level theory offers an alternative explanation. Also, the acute postoperative pain in this study did not seem to induce DNIC. Because other forms of acute pain have been found to be effective in activating DNIC, future research should establish which pains are and which pains are not effective.

Topics: Adult; Aged; Aging; Blood Pressure; Chronic Disease; Electric Stimulation; Electromyography; Heart Rate; Humans; Low Back Pain; Male; Middle Aged; Mouth; Naloxone; Pain Threshold; Pain, Postoperative

In ten chronic uremic patients on regular hemodialysis treatment in vitro experiments revealed that stimulation of opioid receptors with morphine did not significantly change the mitogen-induced proliferative response of peripheral blood lymphocytes and interleukin-2 (IL-2) receptor expression on PHA-stimulated lymphocytes, while it appreciably decreased surface transferrin (Trf) receptor expression on PHA-stimulated lymphocytes. However, metenkephalin inhibited mitogen-induced proliferation and surface Trf receptor expression on uremic lymphocytes without affecting IL-2 receptor expression on PHA-stimulated cells. In ten healthy subjects opioid receptor agonists did not significantly affect mitogen-induced proliferation of lymphocytes, except for the inhibitory effect of 10(-8) M morphine in relation to lymphocytes stimulated with an optimal pokeweed mitogen (PWM) concentration. At the same time, opioid receptor agonists depressed surface IL-2 and Trf receptor expression on PHA-stimulated normal lymphocytes. In most of our experiments naloxone itself, a non-selective competitive opioid receptor antagonist, decreased mitogen-induced lymphocyte proliferation and IL-2 and Trf receptor expression on PHA-stimulated lymphocytes. Moreover, most frequently naloxone did not reverse inhibitory effects of opioid receptor agonists on lymphocytes. The results seem to indicate that opioid receptor stimulation by high metenkephalin concentrations, which are observed in the uremic blood plasma, may share the responsibility for immunodeficiency in chronic uremic patients. Next, in the presence of opioid receptor agonists directions of changes in the mitogen-induced proliferative response may not follow the alterations of IL-2 and Trf receptor expression on both uremic and normal lymphocytes. Finally the results also suggest that naloxone may possibly exert effects which are independent of its action on opioid receptors on lymphocytes.

Topics: Adult; Chronic Disease; Enkephalin, Methionine; Female; Humans; In Vitro Techniques; Lymphocyte Activation; Lymphocytes; Male; Morphine; Naloxone; Receptors, Interleukin-2; Receptors, Opioid; Receptors, Transferrin; Uremia

Our previous pharmacological studies using animals indicated that a systemic administration of L-arginine induces an antinociceptive effect and an increase in the brain level of kyotorphin (L-tyrosinyl-L-arginine) which is an endogenous analgesic peptide and a methionine-enkephalin releaser in the brain. The aims of this study were to investigate the analgesic effect of L-arginine, a precursor of kyotorphin, in persistent pain. We selected 12 patients with various kinds of pain of at least 6 months duration. L-Arginine (10% solution, 300 ml (30 g)/patient) was administered by intravenous drip at a rate of 5 ml (0.5 g)/min during a period of 60-70 min. Pain was assessed by the patient using a 10-cm visual analogue scale (VAS), before and after the L-arginine infusion. L-Arginine treatment resulted in slight analgesia at 10-15 min after the onset of infusion and in marked analgesia at 30-40 min after that. This effect lasted for 6-24 h. L-Arginine-induced analgesia was dose-dependent and blocked by intravenous injection of naloxone. In each case, the L-arginine-induced analgesia was statistically significant as compared with the saline-induced effect. Side effects of L-arginine were a slight decrease in mean blood pressure (10-15 mm Hg), and dryness of the month. A suppressive role of a functional link between the L-arginine-kyotorphin system and the enkephalin system of the brain in persistent pain is suggested.

Topics: Aged; Analgesics; Arginine; Chronic Disease; Cluster Headache; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Naloxone; Pain; Pain Measurement

Previous work in this laboratory has indicated that the transplantation of adrenal medullary tissue into the subarachnoid space of the rat spinal cord can reduce pain sensitivity to acute noxious stimuli, particularly following stimulation by nicotine. This most likely results from the stimulated release of opioid peptides and catecholamines from the transplanted chromaffin cells. However, chronic pain models may more closely resemble human clinical pain, and the arthritic rat model has been used for screening potential therapeutic strategies. The purpose of the present study was to assess the potential for adrenal medullary tissue implanted into the spinal subarachnoid space to alleviate chronic pain. Adrenal medullary tissue was implanted into adjuvant-induced arthritic rats, and changes in body weight and vocalization responses were monitored over the 10 week course of the disease. Results indicate that the severe weight reduction normally associated with this inflammatory arthritis was attenuated by adrenal medullary, but not control, implants. In addition, vocalizations were reduced in animals implanted with adrenal medullary, but not control tissue following nicotine stimulation. This reduction was blocked by the opiate antagonist, naloxone, and partially attenuated by the alpha-adrenergic antagonist, phentolamine. Together, these results suggest that the transplantation of adrenal medullary tissue into the subarachnoid space of the spinal cord may provide a local source of opioid peptides and catecholamines for the reduction of chronic pain.

Topics: Adrenal Medulla; Animals; Arthritis, Experimental; Catecholamines; Chronic Disease; Endorphins; Graft Survival; Male; Naloxone; Pain; Phentolamine; Rats; Rats, Inbred Strains; Spinal Cord; Subarachnoid Space; Transplantation, Heterotopic; Vocalization, Animal; Weight Loss

Intravenous (I.V.) drug users possess a decrease of the monocyte chemotaxis directly related to drug usage. We study the effects of naloxone on monocyte chemotaxis in I.V. drug users, evaluating the chemotactic index and the cellular level of cAMP. The incubation of monocytes with naloxone did not modify the chemotactic index nor the cellular levels of cAMP, the first remaining low and the second high, this being statistically significant compared with the control group. We comment on the possible causes of naloxone's lack of effect and we suggest the role of cAMP in causing the chemotactic defect in this group of patients.

Topics: Chemotaxis, Leukocyte; Chronic Disease; Cyclic AMP; Heroin Dependence; Humans; Methods; Monocytes; Naloxone

Topics: Administration, Oral; Analgesics, Opioid; Chronic Disease; Constipation; Dose-Response Relationship, Drug; Humans; Naloxone; Pain

Beta-endorphin-like immunoreactivity was studied in 7 patients with algomenorrhea during pain attack and 15 minutes after alpha-tocopherol administration with a therapeutic aim (till the analgetic effect was reached). There was an increase in beta-endorphin-like immunoreactivity after alpha-tocopherol administration. Naloxone administration to 9 patients with algomenorrhea of various etiology resumed the pain. The effect of alpha-tocopherol application for pain relief depended on the pathogenesis of algomenorrhea. At the same time naloxone administration failed to resume the pain in patients, in whom alpha-tocopherol had a strong analgetic effect. It is assumed that the endogenous opioid system participates in alpha-tocopherol effect on pain relief in patients with algomenorrhea.

Topics: Adult; alpha-Tocopherol; Analgesia; beta-Endorphin; Chronic Disease; Dysmenorrhea; Endorphins; Female; Humans; Menstruation; Naloxone; Tocopherols; Vitamin E

To assess whether gonadotropin-releasing hormone (GnRH) release from the hypothalamus might be altered by hyperprolactinemia in the male rat, we measured in chronically hyperprolactinemic rats the pituitary GnRH receptor content and described the pattern of luteinizing hormone (LH) release during the postcastration rise in gonadotropin secretion 24 and 72 h after gonadectomy. In intact rats, the effect of hyperprolactinemia was determined by describing the pattern of LH secretion, pituitary GnRH receptor content and assessment of pituitary responsiveness to small doses of GnRH (1.0 ng). In addition, to determine the role endogenous opioids might play in inhibiting GnRH release in hyperprolactinemic rats, we examined the effect of both a continuous infusion and a bolus injection of the opioid antagonist naloxone on the pattern of LH release. Chronic hyperprolactinemia was achieved by implanting 4 pituitaries under the kidney capsules 3-4 weeks before study. Acute hyperprolactinemia was achieved by injecting rats with 1 mg ovine prolactin every 12 h for 3 days. Control animals were untreated or were chronically hyperprolactinemic rats in which the hyperprolactinemia was transiently reversed by treatment for 3 days with the dopamine agonist 2-alpha-bromoergocryptine. The mean LH concentration was greatly decreased at 24 postcastration in chronically hyperprolactinemic rats relative to controls. This decrease was associated with a decrease in LH pulse height and pulse amplitude and pituitary GnRH receptor content, but not with an increase in the LH interpulse interval. In contrast, the decrease in mean LH concentrations in hyperprolactinemic animals at 72 h postcastration was primarily associated with a significantly longer LH interpulse interval than that observed in control animals. Chronic hyperprolactinemia in intact rats decreased the pituitary GnRH receptor content, in addition to decreasing the mean LH concentrations during pulsatile GnRH administration. Chronic hyperprolactinemia also inhibited LH release relative to controls during the continuous 4-hour infusion of naloxone and in response to a bolus injection of naloxone. However, in acutely hyperprolactinemic intact male rats a bolus injection of naloxone increase LH secretion 20 min later to levels similar to those obtained in control rats. In summary, these results indicate that chronic hyperprolactinemia decreased LH secretion by primarily decreasing GnRH secretion as suggested by a decrease in

Topics: Acute Disease; Animals; Chronic Disease; Hyperprolactinemia; Kinetics; Luteinizing Hormone; Male; Naloxone; Orchiectomy; Pituitary Gland; Rats; Rats, Inbred Strains; Receptors, LHRH

Chronic nociception has been studied in male mice by means of the formalin test in which forelimb motor behaviour is scored after subcutaneous formalin injection. The rating remained above 2.0 for 30 min after the injection (scale range 0-3). The magnitude of the nociception has been compared with that reported in other animal types. Mice are more sensitive than rats, cats and monkeys. The stress of a swim of 3 min has been found to reduce nociception by up to 25%. This analgesia is wholly opioid in nature, being abolished by a moderate dose of naloxone (1 mg/kg).

Topics: Animals; Chronic Disease; Endorphins; Male; Mice; Naloxone; Pain; Pain Measurement; Stress, Physiological; Swimming

A series of experiments was conducted in adult male rats to study the development of tolerance to and dependence on morphine in the neural processes controlling LH and prolactin secretion. The central mechanisms controlling both these hormones became tolerant following chronic application of the opiate agonist; this was seen in the form of diminished responsiveness to the agonist with time. There was an apparently greater degree of tolerance in the mechanisms regulating LH secretion than in those regulating prolactin secretion. In parallel experiments, the opiate antagonist naloxone was used to test for the development of dependence in rats chronically treated with morphine. While behavioural signs of physical dependence (withdrawal) were evident, the LH and prolactin responses proved to be the same as those observed in response to acute administration of opiate agonists (i.e. naloxone respectively decreased and increased serum LH and prolactin concentrations in animals chronically treated with morphine). This paper may represent the first report of such paradoxical responses to naloxone. It also demonstrates that opioid tolerance and dependence may exist as two separate phenomena in vivo.

Topics: Animals; Chronic Disease; Luteinizing Hormone; Male; Morphine Dependence; Naloxone; Prolactin; Rats; Rats, Inbred Strains

Inoculation of rats with Mycobacterium butyricum produced an arthritis of the limbs which revealed an enhanced sensitivity to noxious mechanical pressure (hyperalgesia). Arthritic rats displayed a pronounced rise in immunoreactive dynorphin in lumbo-sacral spinal cord which correlated both with the intensity and time-course of this hyperalgesia. MR-2266, a relatively preferential antagonist at the chi-opioid receptor (at which dynorphin is considered to act) potentiated this hyperalgesia. In contrast, MR 2267 (its inactive stereo-isomer) was ineffective. Further, naloxone (a weak chi-antagonist), and ICI 154,129 (a preferential delta-antagonist) were, in each case, inactive. The data demonstrate a pronounced response of spinal dynorphin to chronic arthritic pain in the rat. In addition, they raise the possibility of a function of spinal DYN, via a chi-receptor, in the modulation of chronic arthritic pain.

Topics: Animals; Arthritis; Chronic Disease; Conditioning, Classical; Dynorphins; Enkephalin, Methionine; Mycobacterium Infections; Naloxone; Nociceptors; Pain; Radioimmunoassay; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Spinal Cord

A technique is described which helps in the differentiation between pain of a mainly physical (organic) and emotional (psychogenic) basis. This is based upon the patients' subjective response to the epidural administration of fentanyl and placebo agents. Patients initially had both physical and psychological assessment in a multidisciplinary pain management unit and because of doubt of the underlying diagnosis, were subjected to this procedure. Eight patients are described in whom the following solutions were administered at 20 min intervals: 2 aliquots of normal saline (5 ml) via an epidural catheter; 1 microgram/kg fentanyl via the epidural catheter; intravenous naloxone 0.4 mg, then, depending upon results obtained, 15-20 ml 2% plain lignocaine via the epidural catheter. If a patient's visual analogue score decreased following epidural fentanyl and subsequently increased following naloxone, then a predominantly physical basis for the pain was likely. In contrast, little change in visual analogue score following fentanyl and naloxone suggested a diagnosis of a predominantly emotional basis for the pain. The diagnoses were substantiated by subsequent follow-up and treatment. It is suggested that this test has both prognostic and diagnostic value when used in the context of thorough physical and psychologic assessment of a patient with chronic pain.

Topics: Adult; Aged; Anesthesia, Epidural; Back Pain; Chronic Disease; Diagnosis, Differential; Female; Fentanyl; Humans; Lidocaine; Male; Middle Aged; Naloxone; Pain; Prognosis; Psychophysiologic Disorders; Sensation; Stress, Psychological

Narcotics have been shown to act selectively upon nociceptive synaptic junctions in laminae 1 and 2 of the dorsal horn of the spinal cord. Subarachnoid or epidural injection of narcotics can produce selective segmental analgesia of great intensity and prolonged duration that is free of motor or sympathetic blockade. However, poorly lipid-soluble drugs, such as morphine, that tend to linger in the water phase of the CSF may spread rostrally to involve opiate receptors in brain stem nuclei. Delayed respiratory depression and lifethreatening apnoea is therefore the greatest danger. Other undesirable side effects include itching, nausea and vomiting and urinary retention. All side-effects are antagonized by naloxone. Intraspinal narcotic analgesia has many useful applications for the relief of acute or chronic pain. Obstetrical pain is less amenable to this approach. Effective and safe management of acute pain requires that the patients be under adequate surveillance to avoid the danger of insidious respiratory depression. Chronic malignant pain is well controlled by relatively small doses of narcotic, and these patients can be managed at home on a long-term basis.

Topics: Adjuvants, Anesthesia; Analgesia; Analgesics, Opioid; Anesthesia, Epidural; Anesthesia, Obstetrical; Anesthesia, Spinal; Chronic Disease; Epinephrine; Female; Humans; Male; Naloxone; Pain Management; Pain, Postoperative; Pregnancy; Respiration

In the present study 66 patients suffering from chronic myalgia were given vibratory stimulation as a pain relieving measure. Several of these patients had previously undergone treatments of various kinds without any significant relief. Forty-one patients reported a significant (20%) reduction of pain during vibratory stimulation. The best pain reducing site was found to be either the area of pain, a trigger or acupuncture point outside the painful area. The best pain reducing effect was obtained when the vibratory stimulation was applied with moderate pressure (1.0 kg) over the underlying structures. To obtain a maximal duration of pain relief the stimulation had to be applied for about 30 minutes.

Topics: Adult; Chronic Disease; Female; Humans; Male; Middle Aged; Muscular Diseases; Naloxone; Palliative Care; Vibration

We wished to determine if pain relief that resulted from transcutaneous (TNS) or spinal cord electrical stimulation in patients with chronic pain was due to activation of an endogenous opiate-related pain control system. Naloxone (0.4-10 mg) or saline was injected in double-blind fashion intravenously into opiate-naive subjects with chronic pain who achieved 30% or greater pain relief with spinal cord stimulation (4 patients) or TNS (9 patients). Subjects rated their pain during stimulation and 2, 5, 10 and 15 min after the injection. Two days or more later the procedure was repeated using the alternate agent (naloxone or saline). Naloxone did not decrease the pain relief induced by stimulation, and therefore the effects of stimulation are probably not mediated by the endogenous opiates.

Topics: Chronic Disease; Double-Blind Method; Electric Stimulation Therapy; Endorphins; Epidural Space; Humans; Naloxone; Pain Management; Prospective Studies; Spinal Cord; Transcutaneous Electric Nerve Stimulation

Topics: Chronic Disease; Constipation; Endorphins; Humans; Naloxone

Topics: Antipsychotic Agents; Atrophy; Brain; Cerebral Ventricles; Chronic Disease; Dopamine; Endorphins; GABA Antagonists; gamma-Aminobutyric Acid; Humans; Monoamine Oxidase; Naloxone; Neurotransmitter Agents; Receptors, Dopamine; Schizophrenia

The effect of native serum samples from schizophrenic and control patients on the electrically induced contractions of the isolated mouse vas deferens (MVD) preparations was investigated. It was demonstrated that only the samples of schizophrenic origin elicited a naloxone dependent inhibition on the contractions of the MVD preparations, while sera from healthy individuals and those from non schizophrenic but mentally ill patients proved to be ineffective in this respect. By using ultrafiltration and gel chromatographic techniques, four fractions disclosing MVD related biological activity could be separated from schizophrenic samples. Chemical analysis revealed an elevated quantity of ninhydrin and Lowry positive materials as well as of unidentified carbohydrate components in the active fractions. Molecular mass of the serum ingredients carrying opioid activity was found to range between 0.5 and 5.0 KD. It is speculated that new appearance or the accumulation in the sera of several, and partly at least, unknown peptides and glycopeptides disclosing opioid activity might be characteristic of schizophrenia.

Topics: Animals; Chromatography, Gel; Chronic Disease; Endorphins; Humans; Male; Mental Disorders; Mice; Naloxone; Schizophrenia; Vas Deferens

The influence of a prolonged low frequency electrical stimulation of the somatic afferents on cardiovascular and sympathetic nerve activities was investigated in unanaesthetized spontaneously hypertensive rats (SHRs) and Wistar-Kyoto normotensive rats (WKRs). In SHR, an elevation of blood pressure, heart rate and splanchnic nerve outflow was elicited during a 30-min period of sciatic nerve stimulation. Following the cessation of the stimulation, depressor response and bradycardia slowly developed and lasted up to 12 h. Activation of the group III or A-delta afferent fibers was essential for this post-stimulatory response. The progressive depressor response and a parallelled reduction of the splanchnic nerve activity, reached their maxima at about 1 h after the termination of the sciatic stimulation. The magnitude of the post-stimulatory depressor response was correlated with the prestimulatory control blood pressure level. There were also behavioural changes accompanying the depressor response. The cardiovascular and the behavioural depression were immediately reversed by naloxone (10-15 mg/kg, i.v.). The post-stimulatory depressor response was still present after bilateral sino-aortic denervation, but was absent in animals anaesthetized with chloralose and urethane. Emotional stress produced by air-blowing on the animal resulted in pressor response and tachycardia during the period of the stressful stimulation, but there was no depressor response following the termination of air-blowing. These findings indicate a sympathetic and cardiovascular depression induced by a prolonged stimulation of the somatic group III or A-delta afferent fibers; its long duration and naloxone reversibility suggest the involvement of endorphins in the mechanism of this response. The physiological significance of the effects of the prolonged somatic afferent stimulation and its possible relations with acupuncture are discussed.

Topics: Acupuncture Therapy; Animals; Behavior, Animal; Cardiovascular Diseases; Chronic Disease; Consciousness; Electric Stimulation; Humans; Hypertension; Male; Naloxone; Rats; Rats, Mutant Strains; Sciatic Nerve; Splanchnic Nerves; Stress, Psychological

The effect of nitrous oxide and morphine sulphate on chronic pain states in man are compared. The similarity of effect indicate that nitrous oxide acts on the morphine receptor. In all cases where analgesia was produced naloxone reversal occurred. These results provide additional evidence for a dual system hypothesis of pain perception and that nitrous oxide analgesia is mediated by the endogenous opiate system. In the light of these findings, the possibility of using nitrous oxide to replace morphine sulphate as a screening test for deep brain stimulation analgesia is discussed.

Topics: Adult; Chronic Disease; Female; Humans; Male; Morphine; Naloxone; Nitrous Oxide; Pain, Intractable

Adjuvant-induced arthritic rats were observed clinically and behaviorally. The clinical disease has a duration of greater than 1 month and can be divided into a pre-clinical (1-10 days), an acute (15-30 days), postacute (30-50 days) and a late phase (greater than 50 days). Adjuvant arthritis induces significantly quantitatively changes in the rats' behaviour. Two types of behavioural change merit special attention: freezing (arresting) and scratching. Freezing is significantly increased in the acute and postacute phases; it is increased by morphine, this effect being blocked by naloxone. Scratching is significantly increased in the acute, postacute and late phases; it is decreased by morphine, this effect being blocked by naloxone. The chronic presence of scratching, and the effects of morphine and naloxone on it, allow us to consider it as a possible pain-rated behaviour and therefore as a possible parameter for the study of chronic pain in animals.

Topics: Animals; Arthritis; Arthritis, Experimental; Behavior, Animal; Chronic Disease; Disease Models, Animal; Drug Interactions; Humans; Morphine; Naloxone; Pain; Rats

Topics: Animals; Avoidance Learning; Behavior, Animal; Chronic Disease; Endorphins; Humans; Mental Disorders; Naloxone; Naltrexone; Rats; Receptors, Opioid; Schizophrenia

The nature and extent of enkephalin- and morphine-induced inhibition of pancreatic bicarbonate and protein secretion were studied in dogs with chronic pancreatic fistulae after administering exogenous secretin or octapeptide of cholecystokinin and stimulants for the endogenous release of these hormones. Enkephalin and morphine competitively inhibited the pancreatic bicarbonate secretion induced either by exogenous secretin or duodenal acidification. This inhibition was partially reversed by naloxone, an opiate antagonist. Opiate substance also profoundly inhibited pancreatic protein response to octapeptide of cholecystokinin and to various stimulants of endogenous cholecystokinin release. We conclude that enkephalin and morphine strongly inhibit the pancreatic responses to exogenous and endogenous stimulants by a mechanism involving separate opiate receptors.

Topics: Animals; Bicarbonates; Cholecystokinin; Chronic Disease; Depression, Chemical; Dogs; Dose-Response Relationship, Drug; Duodenum; Endorphins; Enkephalins; Hydrogen-Ion Concentration; Morphine; Naloxone; Pancreas; Peptides; Proteins; Receptors, Opioid; Secretin

Topics: Analgesics, Opioid; Animals; Benzimidazoles; Chronic Disease; Drug Tolerance; Morphine; Naloxone; Pain; Piperidines; Rats; Reaction Time; Time Factors

Topics: Adult; Anxiety; Chronic Disease; Hallucinations; Humans; Injections, Intravenous; Male; Middle Aged; Naloxone; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Tranquilizing Agents

In the context of evaluating the effects of a narcotic antagonist on opiate acquisition, 14 detoxified addicts self-administered increasing doses of unblocked heroin intravenously over a ten-day period. Early in the addiction cycle, subjects experienced tension relief and euphoria but this was followed shortly by a shift in the direction of increasing dysphoria and psychopathology. Nonetheless, individual injections of the drug continued to induce brief episodes of positive mood, an effect enhanced by frequent injection. Heroin self-administration was sharply reduced when subjects were blocked with naltrexone, a narcotic antagonist, and the negative effects observed during unblocked drug use were not observed.

Topics: Acute Disease; Adult; Chronic Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Emotions; Euphoria; Heroin; Heroin Dependence; Humans; Male; Methadone; Morphine; Motor Activity; Naloxone; Naltrexone; Psychopathology