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Opioids and Chronic Nonmalignant Pain

Table of contents



Randomized, placebo-controlled studies


Somatic (non-neuropathic) pain


Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: a double blind, randomized, multicenter, placebo controlled trial. Caldwell JR, Hale ME, Boyd RE, Hague JM, Iwan T, Shi M, Lacouture PG. J Rheumatol. 1999 Apr;26(4):862-9.

Nuts and bolts:
Pros:
Cons:
Bottom line:


Efficacy of controlled-release codeine in chronic non-malignant pain: a randomized, placebo-controlled clinical trial. Arkinstall W, Sandler A, Goughnour B, et al. Pain 1995;62:169-78

Nuts and bolts: This was a randomized, double-blind, placebo controlled, 2-way crossover study that initially enrolled 46 patients diagnosed with chronic non-malignant pain (back pain 9, osteoarthritis 9, fibromyalgia 4). 40% unemployed, 27% workers comp, 13% ongoing litigation, 100% of subjects had had prior opioid exposure with 72.6 +/- 65.8 months duration and 10% having had prior exposure to more potent opioid (morphine). Treatment group received CR codeine (Codeine Contin) at 100mg, 150mg, 200mg q12 hrs, open label use of Tylenol #3 in both groups for breakthrough pain, Visual Analog Scale (VAS, 100mm), 5-point pain categorical scale, Pain Disability Index (PDI), upon completion 28 of 30 patients requested treatment with CR codeine. Treatment group showed statistically lower VAS, categorical pain intensity score, daily rescue analgesic consumption and PDI.
Pros: randomized, placebo-controlled, double-blind, crossover study
Cons: small sample (n=46), large drop out (46 enrolled with 30 completing the study), short duration (7 days pretrial, 7 days (Phase I), 7 days (Phase II)). This study also reports significantly stable long-term pain control, requiring minimal dose adjustment, in patients (n=28) who chose ongoing treatment with CR codeine. However, mean duration reported was 132 days with range of 1-304 days; 15 patients also ended up being treated with CR codeine with mean duration of 431 days making it difficult to reach relevant conclusion about long term efficacy.
Bottom line: CR codeine can provide reduction in pain intensity and disability in patients with chronic non-malignant pain, at least on a short-term basis. This study also provided indirect pharmacodynamic confirmation of CR codeine's 12-hour pharmacokinetic profile through monitoring rescue dose utilization.


Randomised trial of oral morphine for chronic non-cancer pain. Moulin DE, Iezzi A, Amireh R, Sharpe WK, Boyd D, Merskey H. Lancet. 1996 Jan 20;347(8995):143-7.

Nuts and bolts: This was a randomized, double-blind crossover (3 week titration, 6 week evaluation (MS Contin or placebo), 2 week washout) study that initially enrolled 61 patients (43 completed the study) diagnosed with chronic, non-malignant pain (low back, neck, hip, knee) of at least moderate intensity on a categorical scale and greater or equal to 5 on VAS (0-10 cm). 75% unemployed, 28% litigation, opioid naive except for prior history of codeine use, MS Contin bid (up to 60mg bid) vs. Benztropine (active placebo). Paracetamol 500 mg used as rescue medication every four hours. Assessment was performed using Symptom Check List-90 (SCL-90), Profile of Mood States (POMS), Sickness Impact Profile, Pain Disability Index, High Sensitivity Cognitive Screen, VAS, McGill? Pain Questionnaire. MS Contin showed statistically significant analgesic effect in phase I but not in phase II (post crossover). There was no evidence of functional improvement or increased addiction behavior.
Pros: randomized, double-blind, crossover, active placebo controlled study
Cons: 103 patients met inclusion criteria with 42 declining to participate. 43 out of 61 patients completed the study. Short duration of opioid treatment (9 weeks).
Bottom line: MS Contin may provide statistically significant pain relief at least on a short term basis (9 weeks) with low risk of addiction behavior and producing no significant effect on the level of function.


Morphine responsiveness, efficacy and tolerability in patients with chronic non-tumor associated pain — results of a double-blind placebo-controlled trial (MONTAS). Maier C, Hildebrandt J, Klinger R, et al.; MONTAS Study Group. Pain 2002;97:223-33

Nuts and bolts:
Pros:
Cons:
Bottom line:


Efficacy and safety of oxymorphone extended release in chronic low back pain: results of a randomized, double-blind, placebo- and active-controlled phase III study. Hale ME, Dvergsten C, Gimbel J. J Pain. 2005 Jan;6(1):21-8.

Oxymorphone ER has similar efficacy to oxycodone CR and superiority to placebo in randomized, blinded comparisons in patients with chronic low-back pain. Both achieved good pain control once the patient was at a stable dosage. Side effects were similar mostly being constipation and sedation.


Roth SH, Fleischmann RM, Burch FX, Dietz F, Bockow B, Rapoport RJ, Rutstein J, Lacouture PG. 'Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain: placebo-controlled trial and long-term evaluation.' Arch Intern Med. 2000 Mar 27;160(6):853-60.


Cowan DT, Wilson-Barnett J, Griffiths P, Vaughan DJ, Gondhia A, Allan LG. 'A randomized, double-blind, placebo-controlled, cross-over pilot study to assess the effects of long-term opioid drug consumption and subsequent abstinence in chronic noncancer pain patients receiving controlled-release morphine.' Pain Med. 2005 Mar-Apr;6(2):113-21.

Despite arguments that chronic non-cancer pain patients are likely to form addictions to opiods when used as a means to control pain, this study supports the argument that a long-term opiod regimen can be non-addictive and beneficial for chronic pain patients. When patients were transferred from the opioid medication to the placebo, every patient reported an increase in pain, which disrupted their normal sleeping patterns, altered their mood, and changed their ability to function. While the study does add important points to the literature regarding this controversial subject, it’s small sample size does not allow for readers to generalize findings to the greater population.


Peloso PM, Bellamy N, Bensen W, Thomson GT, Harsanyi Z, Babul N, Darke AC. 'Double blind randomized placebo control trial of controlled release codeine in the treatment of osteoarthritis of the hip or knee.' J Rheumatol. 2000 Mar;27(3):764-71.

Neuropathic pain


Watson CP, Babul N. 'Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia.' Neurology 1998;50:1837-41


Gimbel JS, Richards P, Portenoy RK. 'Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial.' Neurology 2003;60:927-34 Full text.

Apart from the average opiod related side effects, patients with diabetic neuropathy who used CR oxycodone reported less pain than those patients who received the placebo. Contrary to the belief that opiods are an ineffective treatment for neuropathic pain, this study demonstrates that with appropriate patient selection, regular monitoring, and management of side-effects, opiods are an effective treatment for diabetic neuropathy. Patients taking CR oxycodone not only had reduced average pain and momentary pain, they also reported satisfaction with study medication and improved sleep quality.

Randomized, controlled studies


Boureau F, Boccard E. Placebo-controlled study of analgesic efficacy of 500 mg paracetamol 30 mg codeine association combined with a low dose of diclofenac versus high dose of diclofenac in rheumatoid arthritis. Acta Ther 1991;17:123-36.

Caldwell JR, Rapoport RJ, Davis JC, Offenberg HL, Marker HW, Roth SH, Yuan W, Eliot L, Babul N, Lynch PM. 'Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: results from a randomized, placebo-controlled, double-blind trial and an open-label extension trial.' J Pain Symptom Manage. 2002 Apr;23(4):278-91.

Jamison RN, Raymond SA, Slawsby EA, Nedeljkovic SS, Katz NP. 'Opioid therapy for chronic noncancer back pain. A randomized prospective study.' Spine. 1998 Dec 1;23(23):2591-600.

In this study researchers compared naproxen, self dose oxycodone, and titrated doses of oxycodone and morphie SR over 16 weeks in patients with chronic non-cancer low back pain. Findings suggest that opiod therapy improves pain and mood but does not consistently improve activity levels. Of those on opiods only one patient reported total elimination of pain but many had low intensity adverse effects. Younger study participants were noted to prefer opiods and have greater urgency to have their pain treated than older patients.

Kjaersgaard-Andersen P, Nafei A, Skov O, Madsen F, Andersen HM, Kroner K, Hvass I, Gjoderum O, Pedersen L, Branebjerg PE. 'Codeine plus paracetamol versus paracetamol in longer-term treatment of chronic pain due to osteoarthritis of the hip. A randomised, double-blind, multi-centre study.' Pain. 1990 Dec;43(3):309-18.

Opioids and NMDA antagonists


Placebo controlled trials


Humans


Frymoyer AR, Rowbotham MC, Petersen KL. 'Placebo-Controlled Comparison of a Morphine/Dextromethorphan Combination With Morphine on Experimental Pain and Hyperalgesia in Healthy Volunteers.' J Pain. 2006 Nov 15; Epub ahead of print

Animals



Meta-analyses


Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. 'Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects.' CMAJ. 2006 May 23;174(11):1589-94. Full text

Neuropathic pain


Eisenberg E, McNicol ED, Carr DB. 'Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials.' JAMA. 2005 Jun 22;293(24):3043-52. Review.


Systematic reviews


Kalso E, Edwards JE, Moore RA, McQuay HJ. 'Opioids in chronic non-cancer pain: systematic review of efficacy and safety.' Pain. 2004 Dec;112(3):372-80. Review.

Chou R, Clark E, Helfand M. 'Comparative efficacy and safety of long-acting oral opioids for chronic non-cancer pain: a systematic review.' J Pain Symptom Manage. 2003 Nov;26(5):1026-48. Review.

Picard PR, Tramer MR, McQuay HJ, Moore RA. 'Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials.' Pain. 1997 Sep;72(3):309-18. Review.

Neuropathic pain


Eisenberg E, McNicol E, Carr DB. 'Opioids for neuropathic pain.' Cochrane Database Syst Rev. 2006 Jul 19;3:CD006146. Review.

Adverse events


Moore RA, McQuay HJ. 'Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids.' Arthritis Res Ther. 2005;7(5):R1046-51. Epub 2005 Jun 28. Review.

Addiction


Hojsted J, Sjogren P. 'Addiction to opioids in chronic pain patients: A literature review.' Eur J Pain. 2006 Oct 25; Epub ahead of print

Functional outcomes and opioid therapy


Positive effect


Simpson RK Jr, Edmondson EA, Constant CF, Collier C. Transdermal fentanyl for chronic low back pain. J Pain Symptom Manage 1997;14:218-24.

Tennant FS Jr, Uelmen GF. Narcotic maintenance for chronic pain: medical and legal guidelines. Postgrad Med 1983;73:81-3, 86-8, 91-4.

Zenz M, Strumpf M, Tryba M. Long-term opioid therapy in patients with chronic nonmalignant pain. J Pain Symptom Manage 1992;7:69-77.

Lack of effect


Caldwell JR, Rapoport RJ, Davis JC, et al. Efficacy and safety of a once-daily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: results from a randomized, placebo-controlled, double-blind trial and an open-label extension trial. J Pain Symptom Manage 2002;23:278-91.

Jamison RN, Raymond SA, Slawsby EA, Nedeljkovic SS, Katz NP. 'Opioid therapy for chronic noncancer back pain. A randomized prospective study.' Spine. 1998 Dec 1;23(23):2591-600.

Moran C. MST continuous tablets and pain control in severe rheumatoid arthritis. Br J Clin Res 1991;2:1-12.

Moulin DE, Iezzi A, Amireh R, et al. 'Randomised trial of oral morphine for chronic non-cancer pain.' Lancet 1996;347:143-7

Raja SN, Haythornthwaite JA, Pappagallo, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2002;59:1015-21.

Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med 2003;348: 1223-32.


Cognition and opioid therapy


Bruera E, Macmillan K, Hanson J, Mac-Donald? RN. The cognitive effects of the administration of narcotic analgesics in patients with cancer pain. Pain 1989;39:13-6.

Galski T, Willimas JB, Ehle HT. Effects of opioids on driving ability. J Pain Symptom Manage 2000;19:200-8.

Haythornthwaite JA, Menefee LA, Quatrano-Piacentini? AL, Pappagallo M. Outcome of chronic opioid therapy for non-cancer pain. J Pain Symptom Manage 1998;15:185-94.

Vainio A, Ollila J, Matikainen E, Rosenberg P, Kalso E. Driving ability in cancer patients receiving long-term morphine analgesia. Lancet 1995;346:667-70.


Opioid-induced hyperalgesia


Brodner RA, Taub A. Chronic pain exacerbated by long-term narcotic use in patients with non-malignant disease: clinical syndrome and treatment. Mt Sinai J Med 1978;45:233-7.

Compton MA. Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status. J Pain Symptom Manage 1994;9:462-73.

Giffard RG, Morgan RL. Cell death in the central nervous system: therapeutic possibilities? Reg Anesth Pain Med 2000;25: 22-5.

Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and opiate tolerance: a current view of their possible interactions. Pain 1995;62:259-74.

Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994;14:2301-12.

Mao J, Sung B, Ji RR, Lim G. Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. J Neurosci 2002;22:7650-61.

Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002;22:8312-23.

Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain 2002;100:213-7.


Opioid-induced hormonal changes


Banki CM, Arato M. Multiple hormonal responses to morphine: relationship to diagnosis and dexamethasone suppression. Psychoneuroendocrinology 1987;12:3-11.

Collu R, Clermont MJ, Ducharme JR. Effects of thyrotropin-releasing hormone on prolactin, growth hormone and corticosterone secretions in adult male rats treated with pentobarbital or morphine. Eur J Pharmacol 1976;37:133-40.

Bartolome MB, Kuhn CM. Endocrine effects of methadone in rats: acute effects in adults. Eur J Pharmacol 1983;95:231-8.

Rolandi E, Marabini A, Franceschini R, Messina V, Bongera P, Barreca T. Changes in pituitary secretion induced by an agonist-antagonist opioid drug, buprenorphine. Acta Endocrinol (Copenh) 1983;104:257-60.

Malaivijitnond S, Varavudhi P. Evidence for morphine-induced galactorrhea in male cynomolgus monkeys. J Med Primatol 1998; 27:1-9.

Mendelson JH, Mendelson JE, Patch VD. Plasma testosterone levels in heroin addiction and during methadone maintenance. J Pharmacol Exp Ther 1975;192:211-7.

Mendelson JH, Meyer RE, Ellingboe J, Mirin SM, McDougle? M. Effects of heroin and methadone on plasma cortisol and testosterone. J Pharmacol Exp Ther 1975;195:296-302.

Rasheed A, Tareen IA. Effects of heroin on thyroid function, cortisol and testosterone level in addicts. Pol J Pharmacol 1995;47:441-4.

Malik SA, Khan C, Jabbar A, Iqbal A. Heroin addiction and sex hormones in males. J Pak Med Assoc 1992;42:210-2.

Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab 2000;85:2215-22.

Finch PM, Roberts LJ, Price L, Hadlow NC, Pullan PT. Hypogonadism in patients treated with intrathecal morphine. Clin J Pain 2000;16:251-4.


Opioid cessation outcome studies


Clark, Michael E. 'Opioid Cessation and Chronic Pain Treatment Outcomes' To evaluate the effects of opioid cessation following comprehensive, multidisciplinary, cognitive behavioral therapy for veterans with severe chronic pain. slide presentation in PDF format


Need categorization


Neuropathic


Rowbotham MC, Twilling L, Davies PS, Reisner L, Taylor K, Mohr D. Oral opioid therapy for chronic peripheral and central neuropathic pain. N Engl J Med 2003;348: 1223-32.

Watson CPN, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998;50:1837-41.

Maier C, Hildebrandt J, Klinger R, Henrich-Eberl? C, Lindena G. Morphine responsiveness, efficacy and tolerability in patients with chronic non-tumor associated pain — results of a double-blind placebo-controlled trial (MONTAS). Pain 2002;97:223-33.

Raja SN, Haythornthwaite JA, Pappagallo, et al. Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2002;59:1015-21.



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