methylnaltrexone and Pain

Opioid-related bowel dysfunction is a common and potentially severe adverse effect from treatment with opioid analgesics. Its development is not dose related, nor do patients develop tolerance. Opioid-induced constipation (OIC) can lead to fecal impaction, bowel obstruction, and bowel perforation as well as noncompliance with opioid analgesics and poor quality of life. Routine administration of laxatives is necessary to maintain bowel function, and, in refractory cases, other modalities must be pursued. Available options are limited but include peripherally acting μ-opioid receptor antagonists (PAMORAs), including methylnaltrexone. Naloxegol is a newly developed PAMORA that is available through the oral route. At the therapeutic dose of 25 mg daily, naloxegol is effective and safe, with a limited side effect profile and is associated with preservation of centrally mediated analgesia. In this article, we discuss the pharmacokinetics, pharmacodynamics, adverse effects, clinical trials, and cost considerations of naloxegol. Finally, we discuss its potential role as a novel key treatment for OIC in palliative medicine patients.

Topics: Analgesics, Opioid; Constipation; Drug Interactions; Humans; Morphinans; Naltrexone; Narcotic Antagonists; Pain; Polyethylene Glycols; Quality of Life; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic

Constipation is a common and often debilitating condition in the elderly, which may be caused by underlying disease conditions, structural abnormalities in the bowel, and a variety of medications such as anticholinergics, antidepressants, and opiates. In this review, we focus on opioid-induced constipation (OIC), which is often underrecognized and undertreated in the elderly. When opioid therapy is initiated, healthcare providers are encouraged to evaluate risk factors for the development of constipation as part of a thorough patient history. To this end, the patient assessment should include the use of validated instruments, such as the Bristol Stool Scale and Bowel Function Index, to confirm the diagnosis and provide a basis for evaluating treatment outcomes. Healthcare providers should use a stepwise approach to the treatment of OIC in the elderly. Conventional laxatives are a first-line option and considered well tolerated with short-term use as needed; however, evidence is lacking to support their effectiveness in OIC. Moreover, because of the risk of adverse events and other considerations, such as chewing difficulties and swallowing disorders, conventional oral laxatives may be inappropriate for the treatment of OIC in the elderly. Thus, the availability of new pharmacologic agents such as the peripherally acting µ-opioid receptor antagonists methylnaltrexone and naloxegol, which target the underlying causes of OIC, and the secretagogue lubiprostone may provide more effective treatment options for elderly patients with OIC.

Topics: Aged; Analgesics, Opioid; Constipation; Health Personnel; Humans; Laxatives; Naltrexone; Narcotic Antagonists; Pain; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Treatment Outcome

Most prescribed opioids exert their analgesic effects via activation of central μ-opioid receptors. However, μ-opioid receptors are also located in the gastrointestinal (GI) tract, and activation of these receptors by opioids can lead to GI-related adverse effects, in particular opioid-induced constipation (OIC). OIC has been associated with increased use of healthcare resources, increased healthcare costs, and decreased quality of life for patients. Nonpharmacologic (e.g., increased fiber uptake) and pharmacologic agents (e.g., laxatives) may be considered for the treatment and prevention of OIC. However, many interventions, such as laxatives alone, are generally insufficient to reverse OIC because they do not target the underlying cause of OIC, opioid activation of μ-opioid receptors in the GI tract. Therefore, there has been keen interest in antagonism of the μ-opioid receptor in the periphery to inhibit the effects of opioids in the GI tract. In this review, currently available pharmacologic therapies for the treatment and prevention of OIC are summarized briefly, with a primary focus on the administration of the peripheral μ-opioid receptor antagonist methylnaltrexone bromide in patients with OIC and advanced illness who are receiving palliative care. Also, clinical trial data of methylnaltrexone treatment in patients with OIC and other pain conditions (i.e., chronic noncancer pain and pain after orthopedic surgery) are reviewed. Data support that methylnaltrexone is efficacious for the treatment of OIC and has a favorable tolerability profile.

Topics: Analgesics, Opioid; Clinical Trials as Topic; Constipation; Dietary Fiber; Humans; Laxatives; Naltrexone; Narcotic Antagonists; Pain; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Opioids are one of the most widely used therapies for the palliative treatment of cancer pain; however, despite their proven analgesic efficacy, they are associated with several adverse effects. Associated with psychological distress and multiple concomitant clinical concerns, constipation is the most commonly occurring adverse effect of chronic opioid therapy in cancer patients. Whilst prophylaxis remains the first-line management option, methylnaltrexone is a recommended treatment option for opioid-related constipation if administration of laxatives is ineffective. Due to its inability to cross the blood-brain barrier, methylnaltrexone exerts a peripheral inhibition of opioid-related effects without influencing the opioid-induced central effects; as a result, the analgesic effect of opioids is unaffected. Moreover, multiple clinical trials, albeit not always conducted specifically in cancer patients, have demonstrated that up to 4 months' treatment with either intravenous or subcutaneous methylnaltrexone provides effective relief from opioid-related constipation and is well tolerated. Preliminary evidence indicates that the addition of methylnaltrexone to standard care for opioid-related constipation may also be advantageous from a pharmacoeconomic perspective. In addition, preliminary data suggest that methylnaltrexone could be associated with some further clinical benefits other than the treatment of opioid-related constipation, such as the improvement of gastric emptying, the relief of nausea/vomiting, and the reduction of the risk of regurgitation and pulmonary aspiration. This narrative review examines the most recent evidence and evaluates the current role of methylnaltrexone in the management of opioid-related constipation, and its potential efficacy in cancer patients. The pharmacokinetics, pharmacodynamics, efficacy and tolerability of methylnaltrexone are discussed.

Topics: Analgesics, Opioid; Constipation; Humans; Naltrexone; Narcotic Antagonists; Neoplasms; Pain; Palliative Care; Quaternary Ammonium Compounds

Pediatric oncology patients can experience opioid-induced constipation, which may not respond to laxative treatment. Methylnaltrexone is an opioid receptor antagonist that can reverse opioid-induced constipation without affecting analgesia. Published literature on the use of methylnaltrexone in children is very limited. This retrospective review describes the effectiveness and safety of methylnaltrexone for opioid-induced constipation in pediatric oncology patients.. A retrospective review of health records was conducted for pediatric oncology in-patients who were prescribed methylnaltrexone between May 2008 and September 2012 at The Hospital for Sick Children. Demographic, clinical, efficacy, and safety data were collected, including; opioid, laxative, and methylnatrexone dosing and frequency.. Fifteen patients (median age: 14 years, range: 4-17 years) received methylnaltrexone; 12 received a single dose while three received multiple doses. At the time of methylnaltrexone administration, patients were receiving a median oral morphine dose equivalent of 5.7 mg/kg/day (range: 1.5-29.2 mg/kg/day) and had not had any bowel movements for several days despite treatment with multiple laxatives. Methylnaltrexone was given at a mean dose of 0.15 ± 0.02 mg/kg/dose (range: 3-12 mg/dose) as a subcutaneous injection. After 14 of 19 doses administered, patients had a bowel movement within 4 hours. Three patients had documented mild gastrointestinal upset following methylnaltrexone administration. None reported a reduction of pain control or opioid withdrawal symptoms.. This case series suggests that methylnaltrexone is safe and may be effective when given subcutaneously as a 0.15 mg/kg single dose to pediatric oncology patients with opioid-induced constipation.

Topics: Adolescent; Analgesics, Opioid; Child; Child, Preschool; Constipation; Female; Humans; Male; Naltrexone; Narcotic Antagonists; Neoplasms; Pain; Quaternary Ammonium Compounds; Retrospective Studies

Methylnaltrexone is effective for opioid-induced constipation (OIC) in advanced illness patients. This 4-week, double-blind, randomized, placebo-controlled study investigated the effect of subcutaneous methylnaltrexone on OIC in patients receiving opioids for chronic, nonmalignant pain. Patients (N = 460) received subcutaneous methylnaltrexone 12 mg once daily (QD) or every other day (alternating with placebo) compared with placebo. Assessments included bowel movement count, time of bowel movement, straining, sense of complete evacuation, Bristol Stool Form Scales, and quality of life. Within 4 hours of first dose, 34.2% of patients in both methylnaltrexone groups had rescue-free bowel movements (RFBMs) versus 9.9% on placebo (P < .001). The estimated number needed to treat was about 4. On average, 28.9% of methylnaltrexone QD and 30.2% of methylnaltrexone alternate-day dosing resulted in RFBMs within 4 hours versus 9.4% QD and 9.3% alternate-day placebo injections (both P < .001). Both methylnaltrexone groups had significantly shorter time to first RFBM (P < .001) and greater increase in number of weekly RFBMs (P < .05) versus placebo. Adverse events included abdominal pain, diarrhea, nausea, and hyperhidrosis. Bristol Stool Form Scale scores (P = .002) and sensation of complete evacuation (P < .04) were significantly superior with methylnaltrexone QD; both methylnaltrexone groups reported no or mild straining during RFBMs in the first 2 weeks (P < .02). At 4 weeks, a significantly greater improvement in patient-reported, constipation-specific quality of life was seen in the alternate-day dosing (P < .05) and QD (P < .001) groups.. We present data demonstrating that subcutaneous methylnaltrexone 12 mg given once daily (QD) or every other day provides significant relief of OIC and was generally well tolerated in patients with chronic, nonmalignant pain. These results expand on prior effectiveness observed for the treatment of OIC in advanced illness patients to a broader population.

Topics: Adult; Aged; Analgesics, Opioid; Chi-Square Distribution; Constipation; Defecation; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Pain; Quaternary Ammonium Compounds; Surveys and Questionnaires; Treatment Outcome

Methylnaltrexone, a peripherally-acting quaternary opioid antagonist, is an investigational treatment for opioid-induced constipation in patients with advanced illness. This randomized, parallel-group, repeated dose, dose-ranging trial included a double-blind phase for one week followed by an open-label phase for a maximum of three weeks. Opioid-treated patients with advanced illness who met criteria for opioid-induced constipation despite laxative therapy were potentially eligible. Double-blind treatment occurred on Days 1, 3, and 5; open-label therapy could be administered as often as every other day. The initial dose range of 1mg, 5mg, or 12.5mg was extended by adding a 20mg group during the study while still maintaining the double blind; the initial open-label dose of 5mg could be titrated. The primary outcome was a laxation response within four hours after the first dose. Thirty-three patients received at least one dose of methylnaltrexone. Only one of 10 patients (10%) who received the 1mg dose experienced laxation within four hours of dosing. The median time to laxation was >48 hours for the 1mg dose group, compared to 1.26 hours for all patients receiving >or=5mg (P=0.0003). There was no apparent dose-response above 5mg. Most adverse events were related to the gastrointestinal system, were mild, and did not lead to discontinuation. In conclusion, methylnaltrexone relieved opioid-induced constipation at doses >or=5mg in patients with advanced illness, and did not reduce analgesia or cause opioid withdrawal symptoms.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Neoplasms; Pain; Pain Measurement; Quaternary Ammonium Compounds; Terminal Care

Opioid-induced constipation (OIC) may occur in up to 81% of critically ill patients and can lead to many complications. Opioid antagonists are a reasonable approach and may be used for managing OIC.. The purpose of this study was to assess the efficacy of enteral naloxone (NLX) versus subcutaneous methylnaltrexone (MNTX) for the management of OIC in critically ill patients.. A retrospective analysis was conducted on adult patients who received NLX or MNTX and a continuous opioid infusion for at least 48 hours. The primary end point was time to resolution of constipation, defined as hours to first bowel movement (BM) after the first dose of an opioid antagonist. Reversal of analgesia was assessed by comparing the total number of morphine milligram equivalents (MME) 24 hours preopioid and postopioid antagonist administration. Univariate and multivariate analyses were conducted to assess treatment response within 48 hours.. The time to first BM was shorter with enteral NLX. Both NLX and MNTX appear to be effective for the management of OIC without causing reversal of analgesia. Future controlled, prospective trials comparing these agents are warranted.

Topics: Adult; Analgesics, Opioid; Constipation; Critical Illness; Humans; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Induced Constipation; Pain; Prospective Studies; Quaternary Ammonium Compounds; Retrospective Studies

Although botulinum toxin type A (BT-A) is approved for chronic migraine treatment, its site and mechanism of action are still elusive. Recently our group discovered that suppression of CGRP release from dural nerve endings might account for antimigraine action of pericranially injected BT-A. We demonstrated that central antinociceptive effect of BT-A in sciatic region involves endogenous opioid system as well. Here we investigated possible interaction of BT-A with endogenous opioid system within the trigeminal region.. In orofacial formalin test we investigated the influence of centrally acting opioid antagonist naltrexone (2 mg/kg, s.c.) versus peripherally acting methylnaltrexone (2 mg/kg, s.c.) on BT-A's (5 U/kg, s.c. into whisker pad) or morphine's (6 mg/kg, s.c.) antinociceptive effect and the effect on dural neurogenic inflammation (DNI). DNI was assessed by Evans blue-plasma protein extravasation.. Naltrexone abolished the effect of BT-A on pain and dural plasma protein extravasation, whereas peripherally acting methylnaltrexone did not change either BT-A's effect on pain or its effect on dural extravasation. Naltrexone abolished the antinociceptive and anti-inflammatory effects of morphine, as well. However, methylnaltrexone decreased the antinociceptive effect of morphine only partially in the second phase of the test and had no significant effect on morphine-mediated reduction in DNI.. Morphine acts on pain in trigeminal region both peripherally and centrally, whereas the effect on dural plasma protein extravasation seems to be only centrally mediated. However, the interaction of BT-A with endogenous opioid system, with consequent inhibition of nociceptive transmission as well as the DNI, occurs primarily centrally.. Botulinum toxin type A (BT-A)'s axonal transport and potential transcytosis suggest that its antinociceptive effect might involve diverse neurotransmitters at different sites of trigeminal system. Here we discovered that the reduction in pain and accompanying DNI involves the interaction of BT-A with central endogenous opioid system (probably at the level of trigeminal nucleus caudalis).

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Botulinum Toxins, Type A; Dura Mater; Male; Migraine Disorders; Morphine; Naltrexone; Narcotic Antagonists; Neurogenic Inflammation; Neuromuscular Agents; Nociception; Pain; Pain Measurement; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Sciatic Nerve; Trigeminal Caudal Nucleus; Trigeminal Nerve

The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double- blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.

Topics: Age Factors; Analgesics, Opioid; Constipation; Defecation; Drug Combinations; Gastrointestinal Tract; Humans; Laxatives; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Predictive Value of Tests; Prevalence; Quaternary Ammonium Compounds; Receptors, Opioid; Risk Factors

Topics: Analgesics, Opioid; Brain Neoplasms; Child; Constipation; Female; Humans; Morphine; Naltrexone; Narcotic Antagonists; Neuroblastoma; Pain; Quaternary Ammonium Compounds

When laxative regimens have failed, methylnaltrexone may be indicated for the relief of opioid-induced constipation (OIC) in patients with advanced illness receiving palliative care.. A cost-benefit analysis (CBA), based on a willingness-to-pay (WTP) approach, was performed to determine if methylnaltrexone should be added to the formulary list of drugs being reimbursed by third-party payers in Canada for the treatment of cancer patients in palliative care suffering from OIC.. The WTP study had two components: a decision board explaining treatment options (Component A) and a questionnaire to measure individual WTP using a bidding game approach (Component B). Component A had two options: Option 1 (laxatives only) and Option 2 (laxatives+methylnaltrexone injection). Only participants choosing Option 2 were invited to complete Component B. The results of the WTP survey were then incorporated into a CBA. Within a hypothetical cohort, additional monthly premiums that individuals were willing to pay for methylnaltrexone were compared with the monthly costs to the insurer for providing methylnaltrexone to all patients who would potentially be using it.. Four hundred one Canadians, of age 18 years and older, were surveyed and yielded a WTP in additional monthly insurance premiums of Canadian dollar (CAD) $8.65 (95% confidence interval: CAD$6.17-CAD$11.13). The CBA resulted in additional CAD$89,307 with a cost of CAD$139,840 and benefits of CAD$229,147. A set of 10,000 Monte Carlo simulations resulted in average CBA savings of CAD$145,011 with a 99.86% probability of dominance.. The present CBA provides pharmacoeconomic evidence for the adoption of methylnaltrexone for treating OIC in terminally ill cancer patients.

Topics: Adolescent; Adult; Age Distribution; Analgesics, Opioid; Constipation; Consumer Behavior; Cost of Illness; Cost-Benefit Analysis; Female; Health Care Costs; Humans; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Neoplasms; Ontario; Pain; Palliative Care; Patient Acceptance of Health Care; Quaternary Ammonium Compounds; Sex Distribution; Socioeconomic Factors; Treatment Outcome; Young Adult

Topics: Analgesics; Animals; Drug Tolerance; Humans; Ketamine; Morphine Dependence; Naltrexone; Narcotic Antagonists; Ondansetron; Pain; Polypharmacy; Quaternary Ammonium Compounds; Serotonin Antagonists

Topics: Analgesics, Opioid; Constipation; Humans; Laxatives; Naltrexone; Narcotic Antagonists; Pain; Palliative Care; Quaternary Ammonium Compounds

Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents; Constipation; Humans; Naltrexone; Narcotic Antagonists; Pain; Piperidines; Pyridines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

To determine if different subtypes of mu-opioid receptors were involved in antinociception induced by endomorphin-1 and endomorphin-2, the effect of pretreatment with various mu-opioid receptor antagonists beta-funaltrexamine, naloxonazine and 3-methylnaltrexone on the inhibition of the paw-withdrawal induced by endomorphin-1 and endomorphin-2 given intracerebroventricularly (i.c.v.) were studied in ddY male mice. The inhibition of the paw-withdrawal induced by i.c.v. administration of endomorphin-1, endomorphin-2 or DAMGO was completely blocked by the pretreatment with a selective mu-opioid receptor antagonist beta-funaltrexamine (40 mg/kg), indicating that the antinociception induced by all these peptides are mediated by the stimulation of mu-opioid receptors. However, naloxonazine, a mu1-opioid receptor antagonist pretreated s.c. for 24h was more effective in blocking the antinociception induced by endomorphin-2, than by endomorphin-1 or DAMGO given i.c.v. Pretreatment with a selective morphine-6 beta-glucuronide blocker 3-methylnaltrexone 0.25mg/kg given s.c. for 25 min or co-administration of 3-methylnaltrexone 2.5 ng given i.c.v. effectively attenuated the antinociception induced by endomorphin-2 given i.c.v. and co-administration of 3-methylnaltrexone shifted the dose-response curves for endomorphin-2 induced antinociception to the right by 4-fold. The administration of 3-methylnaltrexone did not affect the antinociception induced by endomorphin-1 or DAMGO given i.c.v. Our results indicate that the antinociception induced by endomorphin-2 is mediated by the stimulation of subtypes of mu-opioid receptor, which is different from that of mu-opioid receptor subtype stimulation by endomorphin-1 and DAMGO.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Injections, Spinal; Male; Mice; Naloxone; Naltrexone; Oligopeptides; Pain; Pain Measurement; Quaternary Ammonium Compounds; Reflex; Time Factors

Pairings of a sweet taste and injection of morphine result in a learned avoidance of that taste and learned analgesic tolerance. This avoidance is mediated by the drug's peripheral effect, while learned tolerance involves activation of N-methyl-D-aspartate (NMDA) receptors. Exposure to a sweet taste also reduces morphine analgesia. We studied whether this taste-mediated reduction was reversed by an NMDA or peripheral opioid receptor antagonist.. To determine whether an intraoral infusion of saccharin would modulate morphine analgesia in rats, and to study the contribution of NMDA as well as peripheral opioid receptors to this modulation.. Six experiments used the rat's tail-flick response to study the effect of an intraoral infusion of a sodium saccharin solution on morphine analgesia, and the effects of the quaternary opioid receptor antagonist methylnaltrexone as well as the noncompetitive NMDA receptor antagonist MK-801 on this modulation of analgesia.. An intraoral infusion of saccharin reduced the analgesic effects of an intraperitoneal (i.p.) injection of morphine across a range of doses (experiment la), which was not attributable to an influence on tail-skin temperature (experiment 1b). This reduction was mediated by opioid receptors in the periphery and activation of NMDA receptors because morphine analgesia was reinstated by an i.p. injection of either methylnaltrexone (experiment 2a) or MK-801 (experiment 3a), which was not due to the effect of methylnaltrexone (experiment 2b) or MK-801 (experiment 3b) on morphine analgesia in the absence of saccharin.. These results document evidence for an antagonism of morphine analgesia by actions of the drug at peripheral opioid receptors and excitatory amino-acid activity at NMDA receptors. They are discussed with reference to the aversive motivational effects of peripheral opioid receptors and pain facilitatory circuits.

Topics: Analgesia; Analgesics, Opioid; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Morphine; Naltrexone; Narcotic Antagonists; Pain; Pain Measurement; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Saccharin; Sweetening Agents

Topics: Administration, Oral; Adult; Analgesics, Opioid; Breast Neoplasms; Chemistry, Pharmaceutical; Constipation; Female; Humans; Methadone; Naloxone; Naltrexone; Narcotic Antagonists; Pain; Quaternary Ammonium Compounds

Topics: Blood-Brain Barrier; Constipation; Drug Therapy, Combination; Humans; Morphine; Naltrexone; Narcotic Antagonists; Nausea; Neoplasms; Orphan Drug Production; Pain; Quaternary Ammonium Compounds; United States; United States Food and Drug Administration

Earlier research has demonstrated that when rats are placed in a context associated with mild electric shock (1 mA/0.75 sec), environmental cues alone can produce conditional analgesia that suppresses pain sensitivity on the formalin test. This analgesia appears to be mediated by endogenous opioids since it is reversed by the centrally active opioid antagonists naloxone and naltrexone. Two experiments attempted to determine if peripheral or central opioids mediate this analgesia by employing quaternary naltrexone (QNTX), an antagonist which does not readily penetrate the blood-brain barrier at moderate doses. Intracerebroventricularly administered QNTX (10 micrograms) significantly reversed conditional analgesia, whereas intraperitoneally injected QNTX did not affect formalin-induced behavior. These results suggest that the conditional analgesia produced by our procedures is mediated by central, not peripheral, opioid mechanism(s).

Topics: Animals; Brain; Conditioning, Classical; Female; Injections, Intraventricular; Naltrexone; Pain; Quaternary Ammonium Compounds; Rats; Receptors, Opioid