naloxone and Cancer-Pain

Opioids such as oxycodone are recommended in the management of moderate-to-severe, chronic cancer pain. All opioids can potentially cause constipation, which may be a significant barrier to their use. Multiple randomised clinical trials have shown that the use of naloxone as a peripherally acting mu-opioid receptor antagonist, in combination with oxycodone can prevent or reduce opioid-induced constipation while having equivalent analgesic efficacy to oxycodone alone. However, clinical experience has shown that unexpected events may occur in some patients when unrecognized liver impairment is present. We describe the underlying biological reasons and propose simple, but effective steps to avoid this unusual but potentially serious occurrence. In healthy individuals, naloxone undergoes extensive hepatic first pass metabolism resulting in low systemic bioavailability. However, in patients with hepatic impairment, porto-systemic shunting can increase systemic bioavailability of naloxone, potentially compromising the analgesic efficacy of oral naloxone-oxycodone combinations. This reduced first pass effect can occur in a range of settings that may not always be apparent to the treating clinician, including silent cirrhosis, non-cirrhotic portal hypertension and disruption of liver internal vasculature by metastases. Hepatic function test results correlate poorly with presence and extent of liver disease, and are not indicative of porto-systemic shunting. Presence of hepatic impairment should thus be considered when medication-related outcomes with oxycodone-naloxone combination are not as expected, even if liver function test results are normal.

Topics: Analgesics, Opioid; Cancer Pain; Constipation; Delayed-Action Preparations; Humans; Liver Diseases; Naloxone; Neoplasms; Oxycodone; Tablets

Opioids are associated with side effects in the treatment of moderate-to-severe chronic cancer pain. Oral combination of opioid agonist-antagonist oxycodone-naloxone (OXN-PR) attenuates gastrointestinal side effects; however, evidence on high-dose OXN-PR treatment is scant. This study evaluates the efficacy and tolerability of high-dose OXN-PR in chronic cancer pain.. This was a multicenter, prospective 60-day observation on consecutive cancer patients with uncontrolled moderate-severe chronic pain or intolerant to other analgesics, who were switched at entry visit (T0) to OXN-PR ≥80 mg daily. Patients were reassessed 14, 30, 45, and 60 days later (T60). Primary endpoint of the study was analgesic response rate (decrease ≥30% of pain intensity from baseline, measured on a 0-10 numerical rating scale, NRS) after 30 days on OXN-PR. Additional endpoints assessed at every visit were the impact of pain on quality of life (QoL), breakthrough cancer pain (BTCP) episodes, opioid dosage escalation index, bowel dysfunction, safety, and other side effects.. One hundred nineteen patients were included (age 64 ± 12, metastatic disease in 91.6%); 101 of them (84.9%) completed the 60-day observation. At T0, the majority had severe pain (NRS ≥7 in 79.8%; neuropathic features in 83.2%). Response rate at 30-day visit was 79.8% (n = 95). OXN-PR resulted in a significant reduction in pain over time (T0: 7.4 ± 1.3; T60: 3.3 ± 1.8; p < 0.001), and the number of daily (BTCP) declined (3.9 ± 2.2 vs. 2.0 ± 0.6, p < 0.001). Daily dosage of OXN-PR slightly increased (T0: 81.3 ± 6.0; T60: 93.6 ± 34.0; p < 0.001). The impact of pain on QoL abated (p < 0.0001), and bowel function improved overtime (p < 0.001). After the switch to OXN-PR, the number of patients complaining for side effects decreased overall (p < 0.0001); laxatives and antiemetic use also declined significantly.. OXN-PR was highly effective and well tolerated even at high doses in cancer patients with chronic pain. The agonist-antagonist combination rapidly alleviated pain and its impact on life style, reducing the number of BTCP and improving opioid side effects.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Breakthrough Pain; Cancer Pain; Chronic Pain; Constipation; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Laxatives; Male; Middle Aged; Naloxone; Neoplasms; Oxycodone; Pain Management; Pain Measurement; Quality of Life

Controlled-release oxycodone/naloxone (OXN-CR) maintains the effect of opioid-induced analgesia through oxycodone while reducing the occurrence rate of opioid-induced constipation through naloxone. The present study was designed to assess the non-inferiority of OXN-CR to controlled-release oxycodone (OX-CR) for the control of cancer-related pain in Korean patients.. In this randomized, open-labeled, parallel-group, phase IV study, we enrolled patients aged 20 years or older with moderate to severe cancer-related pain [numeric rating scale (NRS) pain score ≥4] from seven Korean oncology/hematology centers. Patients in the intention-to-treat (ITT) population were randomized (1:1) to OXN-CR or OX-CR groups. OXN-CR was administered starting at 20 mg/10 mg per day and up-titrated to a maximum of 80 mg/40 mg per day for 4 weeks, and OX-CR was administered starting at 20 mg/day and up-titrated to a maximum of 80 mg/day for 4 weeks. The primary efficacy endpoint was the change in NRS pain score from baseline to week 4, with non-inferiority margin of -1.5. Secondary endpoints included analgesic rescue medication intake, patient-reported change in bowel habits, laxative intake, quality of life (QoL), and safety assessments.. Of the ITT population comprising 128 patients, 7 with missing primary efficacy data and 4 who violated the eligibility criteria were excluded from the efficacy analysis. At week 4, the mean change in NRS pain scores was not significantly different between the OXN-CR group (n = 58) and the OX-CR group (n = 59) (-1.586 vs. -1.559, P = 0.948). The lower limit of the one-sided 95% confidence interval (-0.776 to 0.830) for the difference exceeded the non-inferiority margin (P < 0.001). The OXN-CR and OX-CR groups did not differ significantly in terms of analgesic rescue medication intake, change in bowel habits, laxative intake, QoL, and safety assessments.. OXN-CR was non-inferior to OX-CR in terms of pain reduction after 4 weeks of treatment and had a similar safety profile. Studies in larger populations of Korean patients with cancer-related pain are needed to further investigate the effectiveness of OXN-CR for long-term pain control and constipation alleviation. Trial registration ClinicalTrials.gov NCT01313780, registered March 8, 2011.

Topics: Adult; Cancer Pain; Female; Humans; Korea; Male; Naloxone; Oxycodone; Quality of Life; Young Adult

Topics: Analgesics, Opioid; Cancer Pain; Chronic Pain; Constipation; Delayed-Action Preparations; Drug Combinations; Female; Humans; Morphine; Naloxone; Oxycodone; Pharmacogenomic Testing; Quality of Life; Tapentadol

Opioid misuse and opioid use disorder (OUD) are important comorbidities in people with advanced cancer and cancer-related pain, but there is a lack of consensus on treatment.. To develop consensus among palliative care and addiction specialists on the appropriateness of various opioid management strategies in individuals with advanced cancer-related pain and opioid misuse or OUD.. For this qualitative study, using ExpertLens, an online platform and methodology for conducting modified Delphi panels, between August and October 2020, we conducted 2 modified Delphi panels to understand the perspectives of palliative and addiction clinicians on 3 common clinical scenarios varying by prognosis (weeks to months vs months to years). Of the 129 invited palliative or addiction medicine specialists, 120 participated in at least 1 round. A total of 84 participated in all 3 rounds.. Consensus was investigated for 3 clinical scenarios: (1) a patient with a history of an untreated opioid use disorder, (2) a patient taking more opioid than prescribed, and (3) a patient using nonprescribed benzodiazepines.. Participants were mostly women (47 [62%]), White (94 (78 [65%]), and held MD/DO degrees (115 [96%]). For a patient with untreated OUD, regardless of prognosis, it was deemed appropriate to begin treatment with buprenorphine/naloxone and inappropriate to refer to a methadone clinic. Beginning split-dose methadone was deemed appropriate for patients with shorter prognoses and of uncertain appropriateness for those with longer prognoses. Beginning a full opioid agonist was deemed of uncertain appropriateness for those with a short prognosis and inappropriate for those with a longer prognosis. Regardless of prognosis, for a patient with no medical history of OUD taking more opioids than prescribed, it was deemed appropriate to increase monitoring, inappropriate to taper opioids, and of uncertain appropriateness to increase the patient's opioids or transition to buprenorphine/naloxone. For a patient with a urine drug test positive for non-prescribed benzodiazepines, regardless of prognosis, it was deemed appropriate to increase monitoring, inappropriate to taper opioids and prescribe buprenorphine/naloxone.. The findings of this qualitative study provide urgently needed consensus-based guidance for clinicians and highlight critical research and policy gaps.

Topics: Analgesics, Opioid; Benzodiazepines; Buprenorphine; Cancer Pain; Consensus; Female; Humans; Male; Methadone; Naloxone; Neoplasms; Opioid-Related Disorders

Lemairamin (also known as wgx-50), is isolated from the pericarps of the Zanthoxylum plants. As an agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), it can reduce neuroinflammation in Alzheimer's disease. This study evaluated its antinociceptive effects in pain hypersensitivity and explored the underlying mechanisms. The data showed that subcutaneous lemairamin injection dose-dependently inhibited formalin-induced tonic pain but not acute nociception in mice and rats, while intrathecal lemairamin injection also dose-dependently produced mechanical antiallodynia in the ipsilateral hindpaws of neuropathic and bone cancer pain rats without affecting mechanical thresholds in the contralateral hindpaws. Multiple bi-daily lemairamin injections for 7 days did not induce mechanical antiallodynic tolerance in neuropathic rats. Moreover, the antinociceptive effects of lemairamin in formalin-induced tonic pain and mechanical antiallodynia in neuropathic pain were suppressed by the α7nAChR antagonist methyllycaconitine. In an α7nAChR antagonist-reversible manner, intrathecal lemairamin also stimulated spinal expression of IL-10 and β-endorphin, while lemairamin treatment induced IL-10 and β-endorphin expression in primary spinal microglial cells. In addition, intrathecal injection of a microglial activation inhibitor minocycline, anti-IL-10 antibody, anti-β-endorphin antiserum or μ-opioid receptor-preferred antagonist naloxone was all able to block lemairamin-induced mechanical antiallodynia in neuropathic pain. These data demonstrated that lemairamin could produce antinociception in pain hypersensitivity through the spinal IL-10/β-endorphin pathway following α7nAChR activation.

Topics: Aconitine; Acrylamides; alpha7 Nicotinic Acetylcholine Receptor; Analgesics; Animals; beta-Endorphin; Cancer Pain; Female; Formaldehyde; Hyperalgesia; Injections, Spinal; Interleukin-10; Male; Mice; Microglia; Minocycline; Naloxone; Neuralgia; Rats; Rats, Wistar; Spinal Cord; Zanthoxylum

Sustained-release buprenorphine is widely used in mice with the intention of providing long-lasting analgesia. Statements about duration of therapeutic efficacy are based on persistence of serum buprenorphine levels over a minimum threshold, but behavioral data demonstrating sustained efficacy is not established. Additionally, chronic opioid exposure can induce tolerance and/or hyperalgesia; mice receiving sustained-release buprenorphine have not been evaluated for these effects. This study assessed clinical efficacy and duration of sustained-release buprenorphine in inflammatory, post-operative, and cancer pain; and screened for centrally-mediated opioid-induced hyperalgesia as well as opioid tolerance. At 1-2 mg/kg sustained-release buprenorphine, statistically significant analgesic efficacy occurred only at time points up to 2 h. These animals showed no changes in von Frey thresholds on the contralateral side, i.e. no centrally-mediated opioid hyperalgesia. To establish whether acute onset opioid tolerance resulted from a single sustained-release buprenorphine administration, we used the tail flick assay, exposing mice to sustained-release buprenorphine or saline on Day 1 and buprenorphine on Day 2. We measured duration and efficacy of 1 mg/kg buprenorphine after 1 mg/kg sustained-release buprenorphine, and also quantified a dose-response curve of buprenorphine (0.1-3 mg/kg) after 2 mg/kg sustained-release buprenorphine. Compared to control animals, mice previously exposed to sustained-release buprenorphine showed diminished analgesic response to buprenorphine; the resultant dose-response curve showed decreased efficacy. Pretreatment with naloxone, an opioid receptor antagonist, blocked sustained-release buprenorphine analgesic action. The short duration of antinociception following administration of sustained-release buprenorphine in mice is caused by the rapid development of tolerance.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Cancer Pain; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Tolerance; Hyperalgesia; Male; Mice; Mice, Inbred C3H; Naloxone; Narcotic Antagonists; Pain Measurement; Pain, Postoperative

Topics: Analgesics, Opioid; Animals; Bone Neoplasms; Cancer Pain; Cell Line, Tumor; Fentanyl; Hydrogen-Ion Concentration; Hyperalgesia; Ligands; Male; Melanoma, Experimental; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Morphinans; Naloxone; Naltrexone; Narcotic Antagonists; Piperidines; Receptors, Opioid, mu

Bone cancer metastasis is extremely painful and decreases the quality of life of the affected patients. Available pharmacological treatments are not able to sufficiently ameliorate the pain, and as patients with cancer are living longer, new treatments for pain management are needed. Decitabine (5-aza-2'-deoxycytidine), a DNA methyltransferases inhibitor, has analgesic properties in preclinical models of postsurgical and soft-tissue oral cancer pain by inducing an upregulation of endogenous opioids. In this study, we report that daily treatment with decitabine (2 µg/g, intraperitoneally) attenuated nociceptive behavior in the 4T1-luc2 mouse model of bone cancer pain. We hypothesized that the analgesic mechanism of decitabine involved activation of the endogenous opioid system through demethylation and reexpression of the transcriptionally silenced endothelin B receptor gene, Ednrb. Indeed, Ednrb was hypermethylated and transcriptionally silenced in the mouse model of bone cancer pain. We demonstrated that expression of Ednrb in the cancer cells lead to release of β-endorphin in the cell supernatant, which reduced the number of responsive dorsal root ganglia neurons in an opioid-dependent manner. Our study supports a role of demethylating drugs, such as decitabine, as unique pharmacological agents targeting the pain in the cancer microenvironment.

Topics: Animals; Antimetabolites, Antineoplastic; beta-Endorphin; Bone Density; Bone Neoplasms; Cancer Pain; Cell Line, Tumor; Culture Media, Conditioned; Decitabine; Disease Models, Animal; Endothelin-1; Female; Ganglia, Spinal; Locomotion; Mice; Mice, Inbred BALB C; Naloxone; Neurons; Quaternary Ammonium Compounds; Receptor, Endothelin B; Weight-Bearing

Prescription opioids are commonly prescribed for the relief of many kinds of pain syndromes, including cancer pain. In order to combat the growing rates of abuse and misuse of prescription opioids, the Centers for Disease Control and Prevention, along with the U.S. Food and Drug Administration and multiple pharmaceutical companies, have implemented many risk mitigation strategies. Abuse-deterrent drug delivery technology and more consistent prescribing of the opioid antagonist, naloxone, are two of the mechanisms of reducing harm in patients on chronic opioid therapy. Abuse-deterrent technology is implemented into different commercially available opioid products with the intent of discouraging manipulation of the opioid or making the use of the manipulated opioid less appealing. Use of the opioid antagonist, naloxone, for reversal of intentional or unintentional opioid overdose is a safe and effective means to reduce potential risk in patients who are on opioids for pain management. These mechanisms have multiple advantages and limitations that influence their practical use specifically in patients with cancer pain. Patients with cancer pain have unique therapeutic needs and goals, and their balance of treatment risks and benefits differs from that of other kinds of chronic pain disorders. This article provides an overview of the advantages and limitations of these specific harm-reduction strategies and provides guidance on how to practically utilize them when caring for patients with cancer pain. IMPLICATIONS FOR PRACTICE: Treating cancer pain has important and unique considerations compared with other chronic, noncancer pain disorders. The use of risk mitigation strategies for opioid prescribing as promoted by the Centers for Disease Control and Prevention does not translate seamlessly to patients with cancer. It is crucial to be wary of the advantages and pitfalls of all risk mitigation strategies related to opioid use in patients with cancer pain. Careful examination of patient-specific risks and benefits should always be considered when implementing pharmacologic treatment and harm-reduction strategies for the management of cancer pain.

Topics: Analgesics, Opioid; Cancer Pain; Humans; Naloxone; Narcotic Antagonists; Opioid-Related Disorders

Pain management in cirrhosis is a clinical challenge. Most analgesics are metabolized in the liver and cirrhosis may deeply alter their concentration, favouring the appearance of side effects. We aimed to assess the efficacy and safety of oral prolonged-release association of oxycodone/naloxone tablets (OXN) in the treatment of moderate/severe cancer pain in cirrhotic patients with metastatic hepatocellular carcinoma (HCC).. We enrolled n = 32 HCC patients with moderate/severe cancer pain unresponsive to paracetamol alone or associated with codeine or tramadol. All patients received an initial OXN dose of 5 mg bid to be gradually increased in case of insufficient analgesia. At baseline and follow-up visits, we evaluated: pain intensity (using the Numerical Rating Scale, NRS), patients' autonomy in daily activities (Barthel Functioning Index); bowel dysfunction (Bowel Function Index, BFI), signs of hepatic encephalopathy (HE) and other opioid-induced side effects.. No clinically significant adverse effects were reported (median follow-up 122 days). No significant worsening of the BFI score was noted and no cases of HE were detected. Two patients (6.3%) discontinued treatment before T14 because of mild nausea and dizziness. The remaining n = 30 patients were assessed for efficacy. Treatment led to a significant reduction in the mean of pain scores both at T14 (-37.1 ± 16.3%, P < .001) and at T28 (-55.6 ± 21.5%, P < .001); Barthel scores showed gradual and significant increase from T0 (81.6 ± 13.0) to T14 (86.5 ± 11.4, P = .001) and to T28 (88.3 ± 13.6, P = .009).. OXN may be considered a safe and effective option in the fragile population of cirrhotic patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Analgesics, Opioid; Cancer Pain; Carcinoma, Hepatocellular; Chronic Pain; Delayed-Action Preparations; Drug Combinations; Female; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Naloxone; Narcotic Antagonists; Oxycodone; Preliminary Data; Quality of Life; Treatment Outcome

Topics: Aged; Cancer Pain; Delayed-Action Preparations; Drug Combinations; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Naloxone; Oxycodone; Pain Management; Retrospective Studies

Fentanyl is an opioid commonly prescribed for cancer pain. Using melanoma-bearing mice, we investigated whether peripheral action would contribute to fentanyl analgesia in cancer pain. Intravenous injection of fentanyl inhibited mechanical nociception in healthy mice, which was markedly inhibited by the opioid antagonist naloxone, but not naloxone methiodide, a peripherally acting opioid antagonist. Melanoma-bearing mice showed mechanical allodynia and spontaneous licking, a pain-related behavior, which were suppressed by intravenous and local injections of fentanyl. Both naloxone and naloxone methiodide inhibited the analgesic effect of intravenous fentanyl to the same degree. Electrophysiological analysis showed that melanoma growth increased the spontaneous and mechanical stimuli-evoked activity of the tibial nerve, which were inhibited by intravenous fentanyl. There was a greater expression of µ- opioid receptors in skin with a melanoma mass than in the contralateral normal skin. In addition, we found µ-opioid receptors in cultured melanoma cells. There was no difference between the number of µ-opioid receptors in the dorsal root ganglia and spinal cord of the melanoma-bearing and contralateral skin side. These results suggest that the analgesic effect of systemic fentanyl is produced via central and peripheral µ- opioid receptors in cancer pain, and cancer cells are a key site of peripheral action.

Topics: Action Potentials; Analgesics, Opioid; Animals; Cancer Pain; Cell Line, Tumor; Disease Models, Animal; Fentanyl; Humans; Hyperalgesia; Injections, Intramuscular; Injections, Intravenous; Male; Melanoma; Mice; Mice, Inbred C57BL; Naloxone; Narcotic Antagonists; Quaternary Ammonium Compounds; Receptors, Opioid; Receptors, Opioid, mu; Skin; Skin Neoplasms; Spinal Cord; Tibial Nerve; Xenograft Model Antitumor Assays

Topics: Aged; Analgesics, Opioid; Cancer Pain; Carcinoma, Ductal; Delayed-Action Preparations; Drug Combinations; Drug Substitution; Female; Humans; Liver Diseases; Naloxone; Oxycodone

Irinotecan-induced gut toxicity is mediated in part by Toll-Like receptor 4 (TLR4) signalling. The primary purpose of this preclinical study was to determine whether blocking TLR4 signalling by administering (-)-naloxone, a TLR4 antagonist, would improve irinotecan-induced gut toxicity. Our secondary aim was to determine the impact of (-)-naloxone on tumour growth.. Female Dark Agouti (DA) tumour-bearing rats were randomly assigned to four treatments (n = 6 in each); control, (-)-naloxone (100 mg/kg oral gavage at -2, 24, 48, and 72 h), irinotecan (175 mg/kg intraperitoneal at 0 h), and (-)-naloxone and irinotecan. Body weight and tumour growth were measured daily, and diarrhoea incidence and severity were recorded 4× per day up to 72 h post-treatment.. At 72 h, all rats that received irinotecan lost weight compared to controls (p = 0.03). In addition, rats that received (-)-naloxone and irinotecan lost significantly more weight compared to controls (p < 0.005) than irinotecan only compared to controls (p = 0.001). (-)-Naloxone did not attenuate irinotecan-induced severe diarrhoea at 48 and 72 h. Finally, (-)-naloxone caused increased tumour growth compared to control at 72 h (p < 0.05) and significantly reduced the efficacy of irinotecan (p = 0.001).. (-)-Naloxone in our preclinical model was unable to block irinotecan-induced gut toxicity and decreased the efficacy of irinotecan. As (-)-naloxone-oxycodone combination is used for cancer pain, this may present a potential safety concern for patients receiving (-)-naloxone-oxycodone and irinotecan concurrently and requires further investigation.

Topics: Animals; Camptothecin; Cancer Pain; Diarrhea; Female; Irinotecan; Naloxone; Rats; Toll-Like Receptor 4

Topics: Analgesics; Animals; Bone Marrow Cells; Bone Neoplasms; Cancer Pain; Cell Differentiation; Cells, Cultured; Disease Models, Animal; Enkephalins; Female; Genetic Therapy; Genetic Vectors; Humans; Hyperalgesia; Injections, Spinal; Naloxone; Pain Threshold; Protein Precursors; Rats; Rats, Sprague-Dawley; Stem Cell Transplantation

The search for new drugs for cancer pain management has been a long-standing goal in basic and clinical research. Classical opioid drugs exert their primary antinociceptive effect upon activating opioid receptors located in the central nervous system. A substantial body of evidence points to the relevance of peripheral opioid receptors as potential targets for cancer pain treatment. Peptides showing limited blood-brain-barrier permeability promote peripheral analgesia in many pain models. In the present study we examined the peripheral and central analgesic effect of intravenously administered biphalin - a dimeric opioid peptide in a mouse skin cancer pain model, developed by an intraplantar inoculation of B16F0 melanoma cells. The effect of biphalin was compared with morphine - a golden standard in cancer pain management. Biphalin produced profound, dose-dependent and naloxone sensitive spinal analgesia. Additionally, the effect in the tumor-bearing paw was largely mediated by peripheral opioid receptors, as it was readily attenuated by the blood-brain-barrier-restricted opioid receptor antagonist - naloxone methiodide. On the contrary, morphine facilitated its analgesic effect primarily by activating spinal opioid receptors. Both drugs induced tolerance in B16F0 - implanted paws after chronic treatment, however biphalin as opposed to morphine, showed little decrease in its activity at the spinal level. Our results indicate that biphalin may be considered a future alternative drug in cancer pain treatment due to an enhanced local analgesic activity as well as lower tolerance liability compared with morphine.

Topics: Analgesia; Analgesics, Opioid; Animals; Blood-Brain Barrier; Cancer Pain; Cell Line, Tumor; Disease Models, Animal; Drug Tolerance; Enkephalins; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Opioid Peptides; Permeability; Quaternary Ammonium Compounds; Receptors, Opioid; Skin Neoplasms