Systematic Review: Opioid Treatment for Chronic Back Pain: Prevalence, Efficacy, and Association with Addiction

The study by Martell et al.[1] is a welcome addition to a number of systemic reviews and summaries[2] which conclude that the efficacy of opioids for chronic non-cancer pain has never been documented over the long-term [e.g. over four months], in contrast to short-term trials. This is of extreme importance because these drugs have been promoted as effective for many chronic pain disorders [well beyond pain related to cancer] but in the absence of evidenced-based studies attesting to long- term efficacy.

Because of the known effects of potent opioids on brain function and the growing body of adverse effects in both the medical literature[3] and the media, a large population of patients with chronic non-cancer pain has been subjected to a class of drugs in which the risks may far outweigh the benefits. This is particularly relevant in patients with non-tissue- related chronic pain of central origin [e.g. non-structural low back pain, fibromyalgia syndrome, tension headache] who have a high incidence of psychiatric comorbidity and substance abuse[4]. Although psychiatric confounders were not specifically addressed in the Martell article, the prevalence of current substance use disorders in this study were as high as 43% with a lifetime prevalence range between 36% to 56%.

Further data is needed to address other pertinent issues related to opioid use for chronic non-cancer pain. These include the following: the emerging recognition of opioid-induced hyperalgesia, determination of the actual incidence of iatrogenic prescription opioid addiction, particularly in those with psychiatric comorbidities, and the diversion of opioids into our streets and schools and whether this could be associated with poor efficacy, multiple side effects, and/or economic motivations in prescription users. Furthermore, there is an important need to address the growing popularity of prescription opioids like OxyContin and Vicodin by teenagers and young adults [who abuse these drugs in the context of a false sense of security which has resulted in numerous instances of addiction, overdose, and death], the problem of drug-related crime often committed by opioid addicts who are also fueling the expanding heroin trade, and the documented mounting volume of opioid-related deaths which according to CDC data has risen from 1942 fatalities in 1999 to 4451 fatalities in 2002[5] and most likely has continued to rise in each subsequent year.

Current studies such as those of Martell et al. and others should serve to reappraise the entire issue of opioid use for chronic non-cancer pain. Hopefully, this may turn more attention to the importance of selectivity in chosing candidates for opioid therapy, and to non-opioid forms of treatment especially beneficial multimodal, non-pharmacological management such as exercise programs and psychological/behavioral strategies.

References:

[1]Martell BA et el. Systemic Review: Opioid treatment for chronic back pain: Prevalence, efficacy, and association with addiction. Ann Intern Med. 2007;146[2]:116-127.

[2]Manchikanti L. Prescription drug abuse: What is being done to address this new drug epidemic? Pain Physician. 2006;9:287-321.

[3]Wang D, Teichtahl H et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest. 2005;128:1348-56.

[4]Chelminski PR et al. A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity. BMC Health Serv Res. 2005;Jan13;5:3.

[5]Paulozzi LJ et al. Increasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf. 2006;15:618-627.

Conflict of Interest:

None declared

We applaud the recent meta-analysis and review by Martell et al. :"Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction" in the January 16 issue. Opioid prescriptions are so commonly diverted that only marijuana is more widely abused by America's teens. This is exemplified by results from the 2005 National Survey on Drug Abuse and Health, revealing that more Americans used prescription-type pain relievers nonmedically for the first time than marijuana for the first time. Legitimate opioid prescription use has dramatically increased apparently with little regard for the associated nonmedial use. Reasons for this increase include the fact that pain is undertreated, poor physician response to educational efforts aimed at physicians to treat pain syndromes, and a lack of pharmaceutical company prescription pain medication development. Oxycodone prescriptions increased 50% from 1999-2002 to 4.6 million, morphine prescriptions increased greater than 50% to 3.8 million and fentanyl prescriptions increased an incredible 150% to 4.6 million.

Conventional wisdom has been that prescription opioids, when taken as prescribed, rarely produce drug abuse or dependence. While this is often the case, we have seen an increasing number of iatrogenic addicts present in need of addiction treatment. We have studied in laboratory models opioid-induced changes and compared opioids in post-withdrawal anhedonia rather than how they are typically studied using hot plate and other analgesia screens. Fentanyl for example, produces a much more profound and prolonged affective withdrawal state than morphine. As opioid medications have been developed to have more analgesic potency, they have not been studied for their propensity to change brain reinforcement systems and induce prolonged abstinence syndromes which may make abuse and dependence more likely.

This review can be used as a foundation for much-needed national guidelines for the treatment of chronic non-cancer pain. Use of fentanyl and other opioid medications in back pain, in addition to not being efficacious (as this article demonstrates), puts many prescription recipients at risk for opioid abuse and dependence. In addition the current flood of opioids puts the community itself at greater risk for nonmedical use. The consequences of the widespread nonmedical use of these potent medicines demands better ways to reduce it without interfering with appropriate medical practice.

Robert L. DuPont, M.D. Founding Director, NIDA President, Institute for Behavior and Health Rockville, MD.

Noni A. Graham, M.P.H. Coordinator of Public Health Research Programs Department of Psychiatry, Division of Addiction Medicine University of Florida College of Medicine Gainesville, FL

Mark S. Gold, M.D. Distinguished Professor & Chief Departments of Psychiatry, Neuroscience, Anesthesiology, Community Health & Family Medicine, Division of Addiction Medicine University of Florida McKnight Brain Institute PO BOX 100183 Gainesville, FL 32610 (352)392-140 [email protected]

References:

Substance Abuse and Mental Health Services Administration. Results from the 2005 National Survey on Drug Use and Health: National Findings (Office of Applied Studies, NSDUH Series H-30, DHHS Publication No. SMA 06 -4195). Rockville, MD. 2006

Compton WM, Volkow ND. Abuse of prescription drugs and the risk of addiction. Drug and Alcohol Depend. 2006; 81:103-7.

Gold MS, Bruijnzeel A, Frost-Pineda K, Jacobs W. Chemical dependency: Opioids. In: Complications in Anesthesia. 2nd ed. Philadelphia: Saunders Elsevier; 2007:119-21.

Bruijnzeel AW, Lewis B, Bajpai LK, Morey TE, Dennis DM, Gold M. Severe deficit in brain reward function associated with fentanyl withdrawal in rats. Biol Psychiatry. 2006;59:477-80.

Coleman JJ, Bensinger PB, Gold MS, Smith DE, Bianchi RP DuPont RL. Can drug design inhibit abuse? Journal of Psychoactive Drugs. 2005;37(4):343-362.

Conflict of Interest:

Dr. DuPont reports support from McNeil Pharmaceuticals for monitoring of nonmedical use of prescription stimulants. He is also Chairman of the Advisory Committee on Prescription Drug Abuse for the Institute for Behavior and Health, Inc. Dr. Gold and Ms. Graham report no competing interests.

After carefully reading the articles and the meta-analysis I concur with the authors. As physicians and care givers it is our responsibility to deliniate the path/course that our patients follow. It has been my experience in the Va system, as well as in the private sector of medicine, that we do prescribe pain medication (opioids analgesics) either for the cover up of a mis-diagnosis or to please the patients. This, at times, is due to pressure. I understand that even today we do not have a single treatment in pain that will result in the cure of pain syndromes, but I believe that this approach should not be a free pass to medication for everyone. But, what we do have is a systematic approach to the treatment of pain syndromes which in most of the cases should not include opioids since in most cases we end up treating the side effect as well. For example hormone therapy (testosterone), psychological, as well as physical addiction, and dependence and diverting. Which in time will render the patient so dependent on his or her medications that he or she will lose all site of the initial goal which was assisting and improving his or her daily living and functional capacity. So in time they can assist him/herself Finally, I think that this kind of review should be done more often so we can re-evaluate our practice goals.

Conflict of Interest:

None declared

Letter to Editor: Martell et al provided a systematic review of opioid treatment for chronic back pain that reports patterns of use, relative outcomes' efficacy, and association with addiction (2007; 146:116-27). It is our earnest hope that this article will dispel myths about failure to treat pain, pseudo- addiction, opiophobia, and the under-prescription of opioids.

Martell et al have addressed multiple techniques employed in the management of chronic back pain. Of note, however, is that they have failed to discuss interventional techniques. In the United States, interventional techniques are frequently used to treat chronic back pain, despite the fact that there is equivocal debate regarding the effectiveness of these approaches (1). Still, by most accounts, interventional techniques do provide moderate long-term relief.

Kuehn (2) has described the contemporary trend toward the escalating number of prescriptions for opioids and the equally prevalent rise in both legitimate and illegitimate use. Yet, despite these trends, it appears that the under-prescription of opioids myth persists. To date, the majority of literature that has addressed such under-prescription has focused on treatment(s) for postoperative, and/or malignant pain.

Recent congressional hearings on prescription drug abuse and progress in meeting and reducing the new epidemic of prescription drug abuse has revealed a number of salient facts including that prescription drug abuse is second only to marijuana abuse, and that prescription drug abuse (especially pain medications) is more likely than marijuana use to lead to subsequent abuse of illegitimate drugs (3). Thus, while it is practically and ethically important to confront the personal and economic impact of chronic pain, we must also focus on the personal toll and costs associated with prescription drug abuse and diversion.

Kuehn et al (2) provided startling statistics that showed that 99% of the global supply of the opioid, hydrocodone was consumed by the American public in 2004. Do these statistics reveal some unnoticed increase in pain? Surely, these data do not support the notion of frank under-prescription of opioids. Instead, it is likely that these figures reflect a rise in inappropriate prescription of opioids, improper patterns of use and compliance, and/or drug diversion. Giordano (4) stated that that these trends may be the effect(s) of an increasingly pervasive market-mentality, consumerism and resulting acquiescence of medical practice. As Giordano noted, it may not be that pain is under-treated, per se, but rather that the medical system fosters inappropriate treatment of the patient in pain, the patient with co-morbid substance abuse issues, and ultimately constricts the therapeutic and moral roles of the physician and healthcare (5).

Federal and state governments can improve incoherent and ineffective prescription drug monitoring programs, and provide necessary data to enable physicians to prescribe opioids in ways that are both technically and ethically appropriate. However, many current programs remain somewhat focused on "catching thieves" rather than protecting the public and enhancing the public good of medicine. The National All Schedules Prescription Electronic Reporting (NASPER) Act of 2005 (6) is a law that provides for the establishment of controlled substance monitoring program in each state, with communication between state programs. The Government Accounting Office (GAO) (7) has demonstrated the effectiveness of this program in states where its policies are enacted with diligence and care.

Laxmaiah Manchikanti, M.D. Medical Director Pain Management Center of Paducah 2831 Lone Oak Road Paducah, Kentucky 42003 Associate Clinical Professor of Anesthesiology and Perioperative Medicine University of Louisville, Kentucky 40292 E-mail: [email protected].

Financial Disclosures: None reported.

1. Boswell MV, Trescot AM, Datta S, Schultz DM, Hansen HC, Abdi S, et al. Interventional Techniques: Evidence-based Practice Guidelines in the Management of chronic spinal pain. Pain Physician. 2007;10:7-112.

2. Kuehn BM. Opioid prescriptions soar: increase in legitimate use as well as abuse. JAMA. 2007;297:249-51.

3. Manchikanti L. Prescription drug abuse: What is being done to address this new drug epidemic? Testimony before the Subcommittee on Criminal Justice, Drug Policy and Human Resources. Pain Physician. 2006;9:287-321.

4. Giordano J. Cassandra's curse: interventional pain management and preserving meaning against a market mentality. Pain Physician. 2006; 9: 167-170

5. Giordano J. Pain, the patient and the physician: philosophy and virtue ethics in pain medicine. In: M. Schatman (ed.) Ethics of Chronic Pain Management. Infortma, NY, 2006, p. 1-18.

6. Manchikanti L, Whitfield E, Pallone F. Evolution of the National All Schedules Prescription Electronic Reporting Act (NASPER): A public law for balancing treatment of pain and drug abuse and diversion. Pain Physician. 2005;8:335-47.

7. US Department of Justice Office of the Inspector General Evaluation and Inspections Division. Follow Up Review of the Drug Enforcement Administration's Efforts to Control the Diversion of Controlled Pharmaceuticals. July 2006.

Conflict of Interest:

None declared

The poor quality and limited generalizability of the nine studies included in Martell and colleagues'(1) assessment substance abuse/addiction prevalence among chronic back pain patients limits the applicability of their findings to clinical practice. Martell and colleagues acknowledge some of these limitations in their text. We will draw attention to additional problems, and propose an alternative method of estimating abuse/addiction risk of individuals taking opioids for chronic back pain.

First, many of the studies determined prevalence of substance abuse/addiction in populations likely to have higher rates than the general population, including populations of veterans (k=3), populations with high rates of psychiatric/psychological disorders (k=3), and populations including patients under evaluation for suspected addiction (k=1). Substance abuse/addiction rates from these populations are probably not generalizable to all chronic back pain patients.

Second, most (k=7) studies did not differentiate pre-existing substance abuse/addiction from iatrogenic substance abuse/addiction. In the two that did, substance abuse/addiction predated back pain onset (and treatment) in 77%(2) of patients in one study, and 98%(3) in the other. This suggests that the majority of substance abuse/addiction problems may predate chronic back pain and related opioid treatment.

Third, much of the substance abuse/addiction data abstracted by Martell and colleagues includes misuse of alcohol, and use of illicit drugs.

Martell and colleagues associate chronic back pain treated with opioids and substance abuse in general; however, we believe that the more relevant clinical question is whether opioid treatment for chronic back pain leads to opioid abuse/addiction. We propose that prospective studies provide the best available source of data, and we turn to the studies used in Martell and colleagues' short-term (1 week - 3 months) efficacy analysis (k=15, n=1,253(4)); as listed in Table 3 of their article) to answer it. Most excluded patients with current (k=1) or any history of substance abuse/addiction (k=8). In the remaining studies (k=6) it was either not reported or unclear whether substance abuse or addiction was an exclusion criterion. Out of the 1,253 patients enrolled in those 15 trials, the development of a possible sign of opioid abuse or addiction was reported in only one patient, a rate of 0.080%. While larger, prospective long-term trials would be more reassuring, this finding suggests the risk of iatrogenic addiction and/or abuse in persons without a history of substance abuse/addiction in short-term treatment for noncancer back pain is probably low, and cannot ethically justify the undertreatment of chronic pain in well-selected patients.

(1) Martell BA, O'Connor PG, Kerns RD, Becker WC, Morales KH, Kosten TR, Fiellin DA. Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Ann Intern Med 2007 Jan 16;146 (2):116-27.

(2) Brown RL, Patterson JJ, Rounds LA, Papasouliotis O. Substance abuse among patients with chronic back pain. J Fam Pract 1996 Aug;43(2):152-60.

(3) Polatin PB, Kinney RK, Gatchel RJ, Lillo E, Mayer TG. Psychiatric illness and chronic low-back pain. The mind and the spine--which goes first. Spine 1993 Jan;18(1):66-71.

(4) Martell and colleagues abstracted data for n=1,256; however, while they identified 9 double-blinded patients, we identified only 6 patients in: Tennant F, Moll D, DePaulo V. Topical morphine for peripheral pain [letter]. Lancet 1993 Oct 23;342(8878):1047-8.

Conflict of Interest:

None declared

We agree with Nobles and Schoelles that it is unfortunate that there are not more high quality studies of the abuse and/or addiction risk of prescribed opioids. We believe that we pointed out the concerning methodologic limitations in our manuscript. We agree with Gold and colleagues that given our understanding of addictive processes and opioids, it is essential that pharmaceutical opioids be evaluated for their impact on the brain's reward systems and their likelihood to induce syndromes that would result in abuse or addiction. Clinicians should know the risk potential of the medications they prescribe. In 2005, an estimated 11.3 million individuals reported non-medical use of prescription pain medications in the past year.(1) The percentage of these individuals who were receiving these medications for pain treatment is not known.

We agree that an important clinical question is whether long-term (e.g. years) opioid treatment for chronic back pain, as can be seen in clinical practice, leads to addictive behaviors. However, we disagree that the best way to estimate this risk is via passive surveillance in short-term randomized clinical trials in which this outcome was neither primary, nor secondary. We note that neither the prospective nor the experimental nature of a study can guarantee the validity of the data. We also note that bias may be introduced since the majority of these trials were funded by pharmaceutical companies. Furthermore, we disagree that the reference group for patients with chronic back pain should be the "general population". The populations represented in the studies included in this portion of our review are clinical rather than experimental populations and therefore are more likely to approximate the chronic back pain patients that are commonly encountered by clinicians. We believe the inclusion of studies conducted at 2 VA sites and in patients with psychiatric comorbidity improves, rather than detracts from the generalizability of our findings.

Pain should be addressed and treated in all patients. However, prior substance abuse primes a patient for a subsequent substance abuse(2-4) and therefore caution should be used in prescribing controlled medications for some patients. Clinicians writing prescriptions for controlled substances should be aware of a patient's prior or current misuse of alcohol and illicit drugs and not dismissed as per Nobles et al. We do not make a causal link between receiving opioids and developing an addictive disorder, but rather report our findings to highlight the need to consider the clinical history of the patient in pain when considering prescribing opioids.

Bridget A. Martell, MD, MA William C. Becker, MD David A. Fiellin, MD

1. U.S. Department of Health and Human Services. Prevalence and recent trends in misuse of prescription drugs. SAMHSA, Office of Applied Studies, http://www.oas.samhsa.gov/prescription/Ch2.htm#2.1.

2. de Wit H. Priming effects with drugs and other reinforcers. Experimental and Clinical Psychopharmacology. 1996;4(1):5-10.

3. Shalev U, Grimm JW, Shaham Y. Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacological Reviews. 2002;54(1):1-42.

4. Stewart J. Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. Journal of Psychiatry & Neuroscience. 2000;25(2):125-136.

Conflict of Interest:

None declared