|Opioids for CRPS? Think again.
By R. Norman Harden, MD
Whether or not to prescribe opioids for chronic and nonmalignant pain conditions, such as CRPS, remains controversial1-3. After years of thoughtless and over-aggressive use of these compounds for pain, most practitioners have become cautious, primarily due to the emergence of serious side effects and adverse events associated with chronic opioid therapy3-6. Although the quality of research addressing this clinical controversy has improved, there still have been no definitive studies performed3,7,8. Nonetheless, this class is sometimes used in complex regional pain syndrome (CRPS) as a “rescue” or an “as needed” medicine.
One has to question when opioids are used in chronic pain maintenance and prophylaxis in CRPS (around-the-clock therapy)9. The standard for scientific evidence of any therapy in medicine is the Randomized Controlled Trial (RCT) and unfortunately, only one has been conducted evaluating the use of any opioid in CRPS. Harke et al studied controlled-release morphine in CRPS and reported no difference in pain reduction when compared to placebo.11,12. In other words, morphine did not relieve CRPS pain in this trial. More research is needed to definitively address this question, considering that the Harke trial was complicated and may have been underpowered12.
There are a few high-quality studies of opioids for neuropathic pain that suggest marginal efficacy13. However, evidence also suggests that neuropathic pain does not respond as well to opioids as nociceptive pain (pain from skin, muscles, joints) and often requires higher doses15, 16. Consequently, neuropathic pain states (especially the neuropathic component of CRPS) often require much higher doses of opioids, which in turn greatly increase the risk of side effects and adverse events. Thus, a very careful and thoughtful analysis of the risk (ie, side effects, adverse events, cost) to benefit (efficacy/effectiveness) ratio is critical in the decision to use opioids in CRPS.
Since there is no evidence supporting the use of opioids in CRPS and the literature is not particularly supportive of opioids for CRPS, we must conclude the Efficacy/Effectiveness (benefit) part of this equation does not favor opioids in the CRPS population9-12. Opioids are clearly not a panacea, and there are many unresolved concerns about longterm efficacy in any chronic condition, efficacy in neuropathy, tolerance, cognitive impairment (especially with “rescue dosing” or initial titration), long-term toxicity and opioid-induced hyperalgesia3,9.
Good practice and common sense requires that we critically and continuously assess the risks and side effects of opioid therapy in order to maintain that primal tenet of medicine and our Hippocratic Oath: “first do no harm.” Furthermore, our patients must be fully informed of the risks considering that there is no compelling research supporting the use of these compounds for CRPS.
Side Effects of Opioid Therapy
The many risks of opioid therapy are well known, from the very common occurrence of constipation and itchiness to the more recently-identified hypogonadism (shrunken testicles)3,17. Long-term cognitive impairment,
personality changes, tolerance, and long-term toxicity are unresolved issues at the moment. Any general pharmacological reference, such as a recent edition of the Physicians’ Desk Reference, will have a good list of the problems associated with opioids. One particular side effect of opioid use in CRPS is opioid-induced hyperalgesia (increased pain perception)18,19. Since hyperalgesia is an important diagnostic and clinical feature of CRPS, it makes little sense to use a class of drugs that cause this symptom for treatment of CRPS. Thus, a CRPS patient on high-dose opioids may have a worsening of signs and symptoms due to opioid therapy. Simply said, high-dose chronic opioid therapy may make CRPS pain worse.
Optimal CRPS care preferably entails the use of non-drug therapies, nonopioid medications for maintenance, and occasional opioids for crisis management, specifically when overwhelming pain prevents progress in functional restoration and if injection therapy has been considered and/or fails20, 21. Opioids should never beused in isolation, and must always be used only with a comprehensive functional restoration program20, 21. Thus, clinicians should not become over-enthusiastic or overzealous about opioids and should keep them in perspective within therapeutic techniques. A critical assessment of the literature and the risk to benefit ratio suggest that opioid therapy in CRPS is extremely questionable.
R. Norman Harden, MD, is the Director for the Center of Pain Studies and holds the Robert G. Addison Chair in Pain Studies at the Rehabilitation Institute of Chicago. Dr. Harden is currently researching medication trials for pain, post-amputation pain, psychological aspects of pain, complex regional pain syndrome (CRPS), fibromyalgia, headache, back and neck surgery, spinal cord injury, and Multiple Sclerosis. Dr. Harden is also currently the Chairman for the Clinical Affairs Committee of the Reflex Sympathetic Dystrophy Association.
1. Butler SH. Opiates for chronic pain: present American controversy. Regul Pept. 1994;52:S295-S296.
2. Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review of the critical issues.
J Pain Sympt Manage. 1996;11(4):203-217.
3. Harden RN. Chronic opioid therapy: another reappraisal. Am Pain Sac Bull. 2002 Jan/Feb.
4. Turner JA, Calsyn DA, Fordyce WE, Ready LB. Drug utilization patterns in chronic pain patients. Pain. 1982;12:357-363.
5. Schug SA, Large RG. Opioids for chronic noncancer pain. Pain Clin Update. 1995;111(3):104.
6. Turk DC, Brody MC. Chronic opioid therapy for
persistent non-cancer pain: Panacea or oxymoron? APS Bull. 1991:1(1):4-7.
7. Wilson PR. Editorial. Opioids and chronic pain. Clin J Pain. 1997;13:1-2.
8. Dubner R. A call for more science, not more rhetoric, regarding opioids and neuropathic pain. Pain.1991:47:1-2.
9. Harden RN. Pharmacotherapy of complex regional pain syndrome. Am J Phys Med Rehabil. 2005;84(3 Suppl):817-828.
10. Hord ED, Oaklander AL. Complex regional pain syndrome: a review of evidence supported treatment options. Curr Pain Headache Rep. 2003;7(3):188-196.
11. Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain
and complex regional pain syndromes. Pain. 1997;73:123-139.
12. Harke H, Gretenkort P, Ladleif HU, Rahman 5, Harke O. The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study. Anesth Analg. 2001;92(2):488-495.
13. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurol. 1998;50(6):1837-1841.
14. Beydoun A. Neuropathic pain: from mechanisms to treatment strategies. J Pain Sympt Manage. 2003;25(5 Suppl):S1-S3.
15. Sindrup SH, Jensen TS. Pharmacologic treatment of pain in polyneuropathy. Neurol. 2000;55(7):915-920.
16. Benedetti F, Vighetti S, Amanzio M, et al. Dose-response relationship of opioids in nociceptive and neuropathic postoperative pain. Pain. 1998;74(2-3):205-11.
17. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3(5):377-384.
18. Mercadante S, Ferrera P, Villari P, Arcuri E. Hyperalgesia: An Emerging Iatrogenic Syndrome. J Pain Sympt Manage. 2003;26(2):769-775.
19. Mao J, Price DD, Mayer DJ. Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain. 1995;62(3):259-274.
20. Stanton-Hicks M, Baron R, Boas R, et
al. Consensus report: complex regional pain syndromes: guidelines for therapy. Clin J Pain. 1998;14(2):155-166.
21. Harden RN. Ed. Complex Regional Pain Syndrome: Treatment Guidelines. Milford, CT:RSDSA Press; 2006.
RSDSA Review. Fall 2007.