Opioids and the Treatment of Chronic Pain: Controversies, Current Status, and Future Directions (2024)

Abstract

Opioids have been regarded for millennia as among the most effectivedrugs for the treatment of pain. Their use in the management of acute severepain and chronic pain related to advanced medical illness is considered thestandard of care in most of the world. In contrast, the long-term administrationof an opioid for the treatment of chronic non-cancer pain continues to becontroversial. Concerns related to effectiveness, safety, and abuse liabilityhave evolved over decades, sometimes driving a more restrictive perspective andsometimes leading to a greater willingness to endorse this treatment. The pastseveral decades in the United States have been characterized by attitudes thathave shifted repeatedly in response to clinical and epidemiologicalobservations, and events in the legal and regulatory communities. The interfacebetween the legitimate medical use of opioids to provide analgesia and thephenomena associated with abuse and addiction continues to challenge theclinical community, leading to uncertainty about the appropriate role of thesedrugs in the treatment of pain. This narrative review briefly describes theneurobiology of opioids and then focuses on the complex issues at this interfacebetween analgesia and abuse, including terminology, clinical challenges, and thepotential for new agents, such as buprenorphine, to influence practice.

Introduction

Opioids play a unique role in society. They are widely feared compounds,which are associated with abuse, addiction and the dire consequences of diversion;they are also essential medications, the most effective drugs for the relief of painand suffering (Portenoy et al, 2004).Historically, concerns about addiction have apparently contributed to theundertreatment of disorders widely considered to be appropriate for opioid therapy,including cancer pain, pain at the end-of-life, and acute pain (Field and Cassel, 1997; ; ; Breitbart et al. 1998; Smithet al., 2008). The use of opioids for chronic non-malignant pain (CNMP)remains controversial (Manchikanti, 2008;McQuay, 1999). Following publication ofreports on the safety and efficacy of opioids prescribed to small numbers ofpatients with CNMP (e.g., Portenoy and Foley,1986; Nyswander and Dole, 1986)and the publication of a seminal article entitled “The Tragedy of NeedlessPain”, (Melzack, 1990), the use ofopioids to treat CNMP began to be more widely practiced and incorporated intoclinical guidelines. Nevertheless, despite the advances in pain medicine and thewider use of opioids for various chronic pain conditions, there is stillconsiderable controversy surrounding the type of conditions that should be treated,whether the treatment can be generally safe and effective in selected patients, andwhat the clinical goals should be (; ; Stretzler & Kosten 2003).

History of Opioids

The Sumerians in Mesopotamia were among the first people identified to havecultivated the poppy plant around 3400 BC. They named it Hul Gil,the “joy plant” (Booth,1986). It eventually spread throughout the ancient world to every majorcivilization in Europe and Asia and was used to treat pain and many other ailments(Schiff, 2002; ; Booth, 1986; ).

Developments in the 19th century transformed the practice of medicine andinitiated the tension between the desire to make available the medicinal benefits ofthese drugs and recognition that the development of abuse and addiction can lead todevastating consequences for individuals and for society at large (Booth, 1986; Musto, 1999):

• In 1803 morphine, an opioid analgesic, was extracted from opiumby Friedrich Serturner of Germany;

• Dr. Charles Wood, a Scottish physician, invented the hyperdermicneedle and used it to inject morphine to relieve pain fromneuralgia;

• Dr. Eduard Livenstein, a German physician, produced the firstaccurate and comprehensive description of addiction to morphine,including the withdrawal syndrome and relapse, and argued that cravingfor morphine was a physiological response.

• Diacetylmorphine (brand name heroin) was synthesized and brieflypromoted as more effective and less addictive than morphine. In theearly 20th century, when heroin was legally marketed in pill form, itwas used by young Americans to elicit intense euphoria by crushing theheroin pills into powder for inhalation or injection (Katz et al., 2007, c.f. Meldrum, 2003; Hosztafi, 2001).

Beginning in the twentieth century, there were many research advances andmajor changes in the way opioids were used for the treatment of pain and addiction(Ballantyne, 2006; Corbett et al., 2006). These included attempts among severalnations and international organizations to control the distribution and use ofopioids (Musto, 1999); the introduction ofopioid maintenance therapy for the treatment of opioid addiction (first withmorphine and later with methadone, LAAM (levo-alpha acetyl methadol) and sublingualbuprenorphine) (; ); the discovery of the endogenous opioids (); and the recognition that pain is a debilitating and destructivedisease and that opioids are essential for the treatment of many forms of acute andchronic pain.

During most of the twentieth century, the widely held perception amongprofessionals in the United States was that the long-term use of opioid therapy totreat chronic pain was contraindicated by the risk of addiction, increaseddisability and lack of efficacy over time. During the 1990’s, a major changeoccurred, driven by a variety of medical and nonmedical factors (see below). The useof opioids for chronic pain began to increase, showing a substantial year-to-yearrise that continues today. This increased use of opioids for legitimate medicalpurposes has been accompanied by a substantial increase in the prevalence ofnonmedical use of prescription opioids (Zacny, etal., 2003). The National Survey on Drug Use and Health reported that thenumber of first time abusers of prescription opioids increased from 628,000 in 1990to 2.4 million in 2004, that emergency room visits involving prescription opioidabuse increased by 45% from 2000 to 2002, and that treatment admissions forprimary abuse of prescription opioids increased by 186% between 1997 and2002 (SAMHSA, 2004a, 2004b). Opioid abuse indices rose most for two frequentlyprescribed opioids, hydrocodone and controlled-release (CR) oxycodone (Cicero, Inciardi, Munoz, 2005). Although theincrease in prescription drug abuse is likely to be multifactorial, it is likely toreflect, in part, changes in available drug formulations and prescribing practicesof opioid medication (Compton and Volkow,2006). This link between increased medical use and increased abuse hasdriven some of the re-examination of the medical role of these drugs. The challenge,of course, is to reduce the likelihood of opioid misuse while not imposing barrierson the legitimate use of opioid medications, acknowledging both that increased abuseis probably inevitable when a psychoactive drug becomes more accessible and thatattempts to control abuse can have the unintentional effects of discouragingtreatment and placing severe restrictions on the medical profession.

Brief Overview of Opioids: Neurobiology and Mechanism of Action

The term opioid refers to all compounds that bind to opiatereceptors. Conventionally, the term opiate can be used to describethose opioids that are alkaloids, derived from the opium poppy; these includemorphine and codeine. Opioids include semi-synthetic opiates, i.e., drugs that aresynthesized from naturally occurring opiates (such as heroin from morphine andoxycodone from thebaine), as well as synthetic opioids such as methadone, fentanyl,and propoxyphene. The term narcotic is a legal designation andshould not be used in the clinical setting; it refers to opioids and a few otherdrugs that are grouped with the opioids by law enforcement.

In the United States, numerous opioids have been commercialized for oral,transdermal and intravenous administration. Oral and transdermal formulations areusually administered for pain in the ambulatory setting. These include combinationproducts, such as those containing hydrocodone and acetaminophen (Vicodin®,Lorset®) or ibuprofen (Vicoprofen®), tramadol and acetaminophen(Ultracet®), oxycodone and acetaminophen or aspirin (Percocet® orPercodan®), and those containing codeine and acetaminophen or aspirin. Thesingle entity formulations on the market include those containing morphine(Avinza®, Kadian®, MS Contin®, MSIR®), oxycodone(OxyContin®), fentanyl (Duragesic®, Actiq®,Fentora®), hydromorphone (Dilaudid®), oxymorphone (Opana®),and methadone.

Opioids act by binding to specific proteins, called opioid receptors.Receptors are widely distributed. Those involved in pain modulation are situated inboth the central nervous system and the peripheral nervous system. These receptorsalso bind endogenous opioid peptides (endorphins), which are involved in painmodulation and numerous other functions in the body. Among these functions are thosemediated by deep structures of the brain, which are involved in the modulation ofreinforcement and reward mechanisms, mood and stress. Opioid receptors are alsofound on cells from the immune system (Bidlack,2000). In studies with rats, activation of these receptors with morphineis associated with varied effects, including sensitization of afferent nerves tonoxious stimuli ().

When an opioid given for pain binds to receptors, analgesia may beaccompanied by any of a diverse array of side effects related to the activation ofreceptors involved in other functions. These may include effects mediated byperipheral or by peripheral and central mechanisms, such as reduced peristalsis(leading to constipation) and itch, or primary central nervous system effects, suchas miosis, (pupillary constriction) somnolence, mental clouding, and respiratorydepression (;). Centralmechanisms also lead to changes associated with hyperalgesia and decreasedresponsiveness to opioids (tolerance) and it has been speculated that opioid-inducedhyperalgesia may be a clinically-relevant phenomenon leading to increased pain insome situations (). Activation of other central nervous system pathways by opioidsalso may produce mood effects, either dysphoria or euphoria.

Presumably, binding to those receptors involved in reinforcement and rewardalso occurs whenever an opioid is taken. In most individuals, when opioids are takento treat pain, there appears to be no overt effect from change in these systems. Insome cases, however, powerful reinforcement occurs, expressed as efforts to repeatthe administration and these reinforcing outcomes may be associated with craving andwith positive mood effects such as euphorigenic or pleasurable effects (Di Chiara, 2002; ). These outcomes, which are uncommonbut potentially serious when they occur (driving the development of an addictivepattern of use), can occur in the presence or absence of pain. Although theseeffects could be associated with iatrogenic addiction, they appear to be rare inpatients who do not have risk factors suggesting the existence of the biologicalsubstrate for opioid-induced craving (see below).

Although several types of opioid receptors exist (e.g., mu, kappa anddelta), opioid drugs largely produce their analgesic and reinforcing effects viaactivation of the mu opioid receptor; thus, opioids used for pain are oftendescribed as, “mu agonists”. Mu drugs that have the ability to fullyactivate opioid receptors (e.g., higher doses produce greater receptor activation ina dose-dependent manner) are referred to as opioid agonists or full mu agonists(such as morphine, oxycodone and methadone). Those opioids that occupy, but do notactivate, receptors are referred to as opioid antagonists (e.g., naltrexone,naloxone); they can reverse the effects of mu opioid agonists. Those opioids thateither have a low intrinsic activity at the mu receptor, or are agonists at anotherreceptor and antagonists at the mu receptor are called agonist-antagonist drugs.Those with a low intrinsic activity are called partial opioid agonists and arecharacterized by a ceiling on most agonist activity, such that increases in dosewill increase the drug’s physiological and subjective effects only to acertain level and further dose increases produce no additional effects ().

These differences in mu receptor interactions are clearly related to theclinical use of opioid drugs and their abuse liability. Agonist-antagonist drugs areless attractive than pure mu agonists to individuals with addiction and no pain.Although other biochemical and molecular processes are presumably relevant tovariation in these effects, relatively little is known about the interactions amongthese processes in humans.

The clinical use of opioid drugs is influenced by a variety of othercharacteristics, including pharmaco*kinetics. With the notable exception of methadoneand buprenorphine, most opioids have relatively short half-lives and this hasnecessitated the development of new delivery systems designed to provide prolongedeffects and a longer dosing interval.

Clinically-relevant physical dependence and tolerance (see below) may occurwith short-term or long-term use of an opioid compound, particularly a pure muagonist. These phenomena, which vary greatly in the clinical setting, representneuroadaptational processes. The neurophysiology of physical dependence andtolerance are closely related to each other and to the phenomenon of opioid-inducedhyperalgesia (Mao, 2002). The possibilitythat opioid administration, particularly at relatively high doses, may lead toincreased pain has contributed to the controversy about opioid therapy fornon-cancer pain, notwithstanding the limited evidence that this phenomenon occurs inclinical settings.

Brief Overview of Chronic Pain

Chronic pain has been described as pain that has persisted for at least 1month following the usual healing time of an acute injury, pain that occurs inassociation with a nonhealing lesion, or pain that recurs frequently over a periodof months. In most clinical and research reports, chronic pain is typically definedas pain that has persisted for at least 3 months ().

The prevalence of chronic pain in the general population is believed to bequite high, although published reports have varied greatly. Cautious cross-nationalestimates of chronic pain range from 10% (Verhaak et al., 1998) to close to 20% (), which wouldrepresent 30 to 60 million Americans. A national survey of 35,000 households in theUS, conducted in 1998, estimated that the prevalence among adults of moderate tosevere non-cancer chronic pain was 9% (American Pain Society, 1999). A large survey (N=18,980) of generalpopulations across several European countries reported that the prevalence forchronic painful physical conditions was 17.1% ().

Chronic pain is a highly complex phenomenon, which may or may not beprimarily driven by tissue injury. Conventionally, the most common forms of chronicpain are divided into those labeled “nociceptive”, or pain caused byongoing stimulation of pain receptors by tissue damage, and those labeled“neuropathic”, or pain presumed to be related to damage to ordysfunction of the peripheral or central nervous system. These categories of painsimplify a complex reality in which both acute and chronic pain are induced bymultiple peripheral and central mechanisms, which continually interact with eachother and with numerous pain modulating systems. The perturbations that ultimatelyresults in pain perception are caused by neurophysiological processes and otherrelated systems. For example, recent evidence has begun to highlight the role ofneuroimmune activation following a tissue injury as an important mechanism in thedevelopment of chronic pain (DeLeo, 2006).The role of cytokines and other inflammatory mediators is obvious in inflammatorynociceptive pains, such as some types of arthritis, but new data suggest an equallysalient role in the development of chronic neuropathic pain associated with centralsensitization of neural pathways following peripheral injury (Deleo, 2006).

All chronic pain is profoundly influenced by psychological processing andresponses ().Pain severity and pain-related functional impairment are often found to beassociated with psychological and social factors, and patients with identicaldiseases associated with pain, such as degenerative disk disease, may vary greatlyin their reports of pain severity and pain behaviors (Aronoff, 1999). There is an extensive literature documenting theimportance of operant conditioning factors (Fordyce,1976) and cognitive-behavioral factors () in the maintenance of chronicpain behaviors.

Chronic pain also is influenced by psychosocial and psychiatricdisturbances, such as cultural influences, social support, comorbid mood disorder,and drug abuse (). Classic studies of pain behavior indicate thatcultural differences in the beliefs and attitudes towards pain (e.g., Zbrowski, 1969) and the social/environmentalcontext of the pain (e.g., Beecher, 1959)have a significant impact on pain behaviors.

The contribution of psychological, social and psychiatric factors should notlead to the conclusion that a pain syndrome is primarily psychogenic. Pain relatedexclusively or primarily to psychological factors occurs, but is far less prevalentthan pain associated with organic processes that are powerfully influenced bypsychosocial mediators and psychiatric comorbidities ().

The “pattern of suffering” or the pain-related disabilitythat often occurs in concert with persistent pain commonly touches on all domains offunction. Patients with chronic pain may demonstrate pain-related interference withability to perform usual activities at home, work, or school; maladaptive ordysfunctional behaviors, social isolation, and poor sleep patterns; and frequenthealth care utilization (). The recognition that acute pain can compromises health has ledmajor medical associations and accreditation committees to designate pain severityas a “fifth vital sign”, along with blood pressure, temperature,heart rate, and respiration (Fishman, 2005).Further recognition of the increased interest in the assessment and management ofpain is underscored by the U.S. Federal Law (Pain Relief Promotion Act of 2000) thatdeclared the first decade of the 21^st century as the Decade of PainControl and Research (Gatchel et al.,2007).

Chronic pain is a major public health problem, which is associated withdevastating consequences to patients and families, a high rate of health careutilization, and huge society costs related to lost work productivity. The existingtreatments for chronic pain are unable to address the problem and better therapiesare urgently needed. The need for these therapies is the backdrop for the expandinguse of opioid drugs. An extensive clinical experience indicates that long-termopioid therapy is able to help selected patients have a better quality of life, lessuse of health care, and improved productivity. The medical community is no longerdebating the reality of these outcomes, but rather, is now focused on a morefruitful debate about patient selection and the benefits and burdens of these drugsin varied subpopulations. Whether the frame of reference is the individual patientand family, or society-at-large, the issue is about balancing the potential benefitsof these drugs in the large and diverse population with chronic pain with itspotential risks.

Terminology of Opioid Abuse: Dependence, Tolerance, Addiction

Concerns that addiction is a frequent iatrogenic consequence of the medicaluse of opioids may partially be attributed to confusion over terminology, as a wellas failure to recognize that both addiction and chronic pain have a multifactorialetiology. In an effort to develop universal agreement on terminology related toaddiction, the American Academy of Pain Medicine (AAPM), the American Pain Society(APS), and the American Society of Addiction Medicine (ASAM) approved a consensusdocument that clarified this terminology (ASAM,2001; Savage, 2003).

According to the consensus document, tolerance is definedas a decreased subjective and objective effect of the same amount of opioids usedover time, which concomitantly requires an increasing amount of the drug to achievethe same effect. Although tolerance to most of the side effects of opioids (e.g.,respiratory depression, sedation, nausea) does appear to occur routinely, there isless evidence for clinically significant tolerance to opioids– analgesiceffects (Collett, 1998; Portenoy et al., 2004). For example, there are numerousstudies that have demonstrated stable opioid dosing for the treatment of chronicpain (e.g., Breitbart, et al., 1998; Portenoy et al., 2007) and methadonemaintenance for the treatment of opioid dependence (addiction) for extended periods(Strain and Stitzer, 2006). However,despite the observation that tolerance to the analgesic effects of opioid drugs maybe an uncommon primary cause of declining analgesic effects in the clinical setting,there are reports (based on experimental studies) that some patients will experienceworsening of their pain in the face of dose escalation (Ballantyne, 2006). It has been speculated that some of thesepatients are not experiencing more pain because of changes related to nociception(e.g. progression of a tissue-injuring process), but rather, may be manifesting anincrease in pain as a result of the opioid-induced neurophysiological changesassociated with central sensitization of neurons that have been demonstrated inpreclinical models and designated opioid-induced hyperalgesia (Mao, 2002; ). Analgesic tolerance and opioid-induced hyperalgesia arerelated phenomena, and just as the clinical impact of tolerance remains uncertain inmost situations, the extent to which opioid-induced hyperalgesia is the cause ofrefractory or progressive pain remains to be more fully investigated.Physical dependence represents a characteristic set of signsand symptoms (opioid withdrawal) that occur with the abrupt cessation of an opioid(or rapid dose reduction and/or administration of an opioid antagonist). Physicaldependence symptoms typically abate when an opioid is tapered under medicalsupervision. Unlike tolerance and physical dependence which appear to be predictabletime-limited drug effects, addiction is a chronic disease that“represents an idiosyncratic adverse reaction in biologically andpsychosocially vulnerable individuals” (ASAM,2001).

The distinction between physical dependence and addiction is not always madeclear in the pain literature (Ferrell, McCaffery,Rhiner, 1992). Most patients who are administered opioids for chronicpain behave differently from patients who abuse opioids and do not ever demonstratebehaviors consistent with craving, loss of control or compulsive use (e.g., Cowan et al., 2001). Of course, pain andaddiction are not mutually exclusive and some patients who are treated for pain dodevelop severe behavioral disturbances indicative of a comorbid addictivedisorder.

Some patients who are treated with opioids for pain display problematicbehaviors that, on careful assessment, do not reflect addiction, but rather, appearto relate to a different process. This may be another psychiatric disorderassociated with impulsive drug-taking, an unresolved family issue, a disorder ofcognition, or criminal intention. In addition, there appear to be some patients whoengage in problematic behaviors related specifically to desperation about unrelievedpain. The term pseudoaddiction was coined to describe the latterphenomenon ().

Behaviors that may represent pseudoaddiction and behaviors that reflectaddiction or some other serious psychopathology can occur simultaneously, andpresumably, one type of phenomenon may incite the others. The diagnosis of these andother conditions may be challenging and requires a careful assessment of clinicalphenomenology, specifically a range of drug-related behaviors during treatment witha potentially abusable drug (Portenoy, 1994,Lue, Passik, & Portenoy, 1998).

The term aberrant drug-related behaviors has been used toindicate the broad array of problematic nonadherence behaviors (), the nature of which is uncertain until a diagnosis can bedeveloped based on astute clinical assessment. Some aberrant drug-related behaviorstrongly suggests the existence of addiction. These may include the use ofalternative routes of administration of oral formulations (e.g., injection orsniffing), concurrent use of alcohol or illicit drugs, and repeated resistance tochanges in therapy despite evidence of adverse effects; examples of aberrantbehavior less suggestive of addiction are drug hoarding during periods of reducedsymptoms, occasional unsanctioned dose escalation, and aggressive complaining aboutthe need for more drugs (Portenoy,1994).

Distinction between Withdrawal and Chronic Pain

Because addiction is associated with psychological distress and physicaldiscomfort in the form of opioid withdrawal symptoms, it may be difficult todistinguish primary chronic pain complaints from withdrawal pain. Withdrawal alsomay have the potential to increase baseline pain related to other processes. Forexample, based on anecdotal evidence from chronic pain patients, withdrawal fromopioids can greatly increase pain in the original pain site. These phenomena suggestthe need to carefully assess the potential for withdrawal during long-term opioidtherapy (e.g, at the end of a dosing interval or during periods ofmedically-indicated dose reduction).

These phenomena notwithstanding, there also is evidence that experienceddrug abusers are able to distinguish withdrawal pain from chronic pain. For examplein studies of methadone maintenance patients, both the phenomenology and correlatesof chronic pain were different than for withdrawal pain (Karasz et al., 2004; Rosenblumet al., 2003). Chronic pain is typically localized (e.g., back pain,headache) and persists (although with varying degrees of severity) for long periodsof time (). Although certain subjective experiences of withdrawal (e.g.,muscle ache) are similar to some distinct pain syndromes, other withdrawalexperiences such as yawning, sweating and hot and cold flashes are likely to be morecommonly associated with subjective drug withdrawal than with primary painconditions. Moreover, the constellation of words used to describe withdrawal pain islikely to be different than words used to describe other painful disorders.Qualitative studies of addicts going through withdrawal typically refer to theexperience as “being sick” (similar to a moderate to severe flu-likeillness) and not as representing a distinct pain (Farrell, 1994). The subjective experience of withdrawal can be validlymeasured with an instrument such as the Subjective Opiate Withdrawal Scale (SOWS;Handelsman, et al., 1987). Withdrawalfrom short-acting opioids, such as heroin, is typically short-lived; physicalsymptoms are likely to reach their maximum intensity over a 36–72 hourperiod and to reduce in intensity after that (Farrell, 1994).

Co-occuring Chronic Pain and Opioid Addiction

The prevalence of addictive disorders among chronic pain patients isdifficult to determine (Covington and Kotz2003). One 1992 literature review found only seven studies that utilizedacceptable diagnostic criteria and reported that estimates of substance usedisorders among chronic pain patients ranged from 3.2% –18.9% (). A Swedish study of 414 chronic pain patients reportedthat 32.8% were diagnosed with a substance use disorder (). In two US studies, 43 to 45% of chronic pain patientsreported aberrant drug-related behavior; the proportion with diagnosable substanceuse disorder is unknown (Katz et al., 2003;Passik et al., 2004). All these studiesevaluated patients referred to pain clinics and may overstate the prevalence ofsubstance abuse in the overall population with chronic pain.

A relatively high prevalence of substance abuse disorders among persons withchronic pain can also be inferred by the high co-occurrence of these two disorders.There have been several reports that the prevalence of chronic pain among personswith opioid and other substance use disorders is substantially higher than the painprevalence found in the general population (Breitbart, et al., 1996; ; ; Rosenblum et al., 2003; Sheu, et al.,2008).

Opioid Treatment for Chronic Pain

Opioid therapy is the mainstay approach for the treatment of moderate tosevere pain associated with cancer or other serious medical illnesses (; World Health Organization, 1996). Although theuse of opioid analgesics for the treatment of CNMP has been increasing in recentyears () and has been endorsed by numerous professional societies (AAPM, APS, 1997; American Geriatric Society, 1998; PainSociety, 2004), the use of opioids remains controversial due to concernsabout side effects, long-term efficacy, functional outcomes, and the potential fordrug abuse and addiction. The latter concerns are especially evident in thetreatment of CNMP patients with substance use histories (Savage, 2003).

Other concerns that may contribute to the hesitancy to prescribe opioids maybe related to perceived and real risks associated with regulatory and legal scrutinyduring the prescribing of controlled substances (Office of Quality Performance, 2003). These concerns have propelledextensive work to develop predictors of problematic behaviors or frank substanceabuse or addiction during opioid therapy. Questionnaires to assist in thisprediction and monitoring have been developed and used in research and field trials.Examples include the Prescription Drug Use Questionnaire (PDUQ; Compton et al., 1998); the Pain Assessment andDocumentation Tool (PADT; Passik et al.,2004) and the Current Opioid Misuse Measure (COMM; Butler et al., 2007). These instruments are not used inpractice settings at this time.

Narrative reports on the use of opioids for CNMP have underscored theeffectiveness of opioid therapy for selected populations of patients and therecontinues to be a consensus among pain specialists that some patients with CNMP canbenefit greatly from long-term therapy (; Trescot et al.,2006). This consensus, however, has received little support in theliterature. Systematic reviews on the use of opioids for diverse CNMP disordersreport only modest evidence for the efficacy of this treatment (Trescot et al., 2006; 2008). For example, a review of 15 double-blind, randomizedplacebo-controlled trials reported a mean decrease in pain intensity ofapproximately 30% and a drop-out rate of 56% only three of eightstudies that assessed functional disturbance found improvement ().A meta-analysis of 41 randomized trials involving 6,019 patients found reductions inpain severity and improvement in functional outcomes when opioids were compared withplacebo (). Among the 8 studies that compared opioids with non-opioidpain medication, the six studies that included so-called “weak”opioids (e.g., codeine, tramadol) did not demonstrate efficacy, while the two thatincluded the so-called “strong” opioids (morphine, oxycodone) wereassociated with significant decreases in pain severity. The standardized meandifference (SMD) between opioid and comparison groups, although statisticallysignificant, tended to be stronger when opioids were compared with placebo (SMD =0.60) than when strong opioids where compared with non-opioid pain medications (SMD= 0.31). Other reviews have also found favorable evidence that opioid treatment forCNMP leads to reductions in pain severity, although evidence for increase infunction is absent or less robust (; ). Little or no support for the efficacy ofopioid treatment was reported in two systematic reviews of chronic back pain (; Martell, et al.,2007). Because patients with a history of substance abuse typically areexcluded from these studies, they provide no guidance whatsoever about theeffectiveness of opioids in these populations.

Adding further to the controversy over the utility of opioid analgesics forCNMP is the absence of epidemiological evidence that an increase in the medical useof opioids has resulted in a lower prevalence of chronic pain. Noteworthy is aDanish study of a national random sample of 10,066 respondents (). Denmark is known for having an extremely high nationalusage of opioids for CNMP and this use has increased by more than 600%during the past two decades (Eriksen, 2004).Among respondents reporting pain (1,906), 90% of opioid users reportedmoderate to very severe pain, compared with 46% of non-opioid users; opioiduse was also associated with poor quality of life and functional disturbance (e.g.,unemployment).

Although this epidemiological study may be interpreted as demonstrating thatopioid treatment for CNMP has little benefit, the authors acknowledge that thesedisquieting findings do not indicate causality and could be influenced by thepossibility of widespread undertreatment, leading to poorly managed pain. Thislatter interpretation is supported by a commentary on the Ericksen et al. study(Keane, 2007). Keane notes that among the228 pain patients receiving opioids only 57 (25%) were using strong opioids,while the remainder was using weak opioids. European (as well as United States)clinical guidelines generally recommend long-acting formulations of strong opioidsfor the treatment of chronic moderate to severe pain, which may be supplemented withshort-acting opioids for breakthrough pain (PainSociety, 2004; OQP, 2003; Gourlay, 1998; Vallerand, 2003; ).

The possibility of inappropriate opioid treatment is further supported byanother Danish study that assigned pain patients who were on opioid therapy toeither a multidisciplinary pain center (MPC) or to general practitioners (GP) whohad received initial supervision from the MPC staff (). At intake, a substantialnumber of patients in both groups were apparently receiving inappropriate opioidtherapy for chronic pain (60% were being treated with short-acting opioidsand 49% were taking opioids on demand). At the 12 month follow-up,86% of MPC patients were receiving long-acting opioids and 11% tookopioids on demand. There was no change in the administration pattern in the GPgroup. These findings suggest that a significant proportion of opioid-treated CNMPpatients may be receiving inappropriate opioid treatment and that educating generalpractitioners in pain medicine may require more than initial supervision.

It is generally acknowledged that there is a wide degree of variance in theprescribing patterns of opioids for chronic pain (; Trescot et al., 2006). Some opioid treatment practices persist despiteevidence that they might be harmful or have little benefit, such as theover-prescribing of propoxyphene among the elderly (; ). Nursing home patients beingtreated with opioids have been found to be inadequately assessed for pain and to bemore likely treated with short-acting rather than long acting opioids (). Asubstantial number of physicians are reluctant or unwilling to prescribe long-actingopioids to treat CNMP, even when it may be medically appropriate (Nwokeji, et al., 2007).

Controversy about the long-term effectiveness of opioid treatment also hasfocused on the potential clinical implications of opioid-induced hyperalgesia. Asnoted earlier, exposure to opioids can result in an increased sensitivity to noxiousstimuli in animals, and an increased perception of some types of experimental painin humans (c.f., ; ).Anecdotal reports of hyperalgesia occurring with very high or escalating doses ofopioids () has beenviewed as a clinical correlate of these experimental findings. The extent to whichthis phenomenon is relevant to the long-term opioid therapy administered to mostpatients with chronic pain is unknown. Although experimental evidence suggests thatopioid-induced hyperalgesia might limit the clinical utility of opioids incontrolling chronic pain (), there have been no reports of observations in the clinicalliterature to suggest that it should be a prominent problem. More research is neededto determine whether the physiology underlying opioid-induced hyperalgesia may beinvolved in a subgroup of patients who develop problems during therapy, such as lossof efficacy (tolerance) or progressive pain in the absence of a well definedlesion.

Outcome studies of long term use of opioids are compromised bymethodological limitations which make it difficult to acquire evidence of efficacy(Noble, Tregear, Treadwell, & Schoelles, 2007). Methodological limitationsmay be unavoidable because of the ethical and practical challenges associatedrigorous studies such as randomized controlled trials. Guidelines for opioid therapymust now be based on limited evidence; future evidence may be acquired by utilizingother study designs (Noble et al., 2007) such as practical clinical trials (). Thesestudies should include at least three criteria to reflect a positive treatmentresponse: i.e., reduction of pain severity (derived from subjective reports orscores on pain scales), recovery of function (improved scores on instruments thatmeasure some aspect of function), and quality of life.

Guidelines for the use of opioids for the treatment of chronic pain havebeen published (AAFP et al.,1996–2002; OQP, 2003), andrecent guidelines have emphasized the need to initiate, structure and monitortherapy in a manner that both optimizes the positive outcomes of opioid therapy(analgesia and functional restoration) and minimize the risks associated with abuse,addiction and diversion (Portenoy et al.,2004). These guidelines discuss patient selection (highlighting thelikelihood of increased risk among patients with prior histories of substance usedisorders), the structuring of therapy to provide an appropriate level of monitoringand a presumably lessened risk of aberrant drug-related behavior, the ongoingassessment of drug-related behaviors and the need to reassess and diagnose shouldthese occur, and strategies that might be employed in restructuring therapy shouldaberrant behaviors occur and the clinician decide to continue treatment. They alsonote that therapy should be undertaken initially as a trial, which could lead to thedecision to forego more therapy, and that an “exit strategy” must beunderstood to exist should the benefits in the individual be outweighed by theburdens of treatment.

The relatively recent recognition that guidelines for the opioid treatmentof chronic pain must incorporate both the principles of prescribing as well asapproaches to risk assessment and management may represent an important turningpoint for this approach to pain management. Acknowledging that prescription drugabuse has increased during the past decade, a period during which the use of opioidtherapy by primary care physicians and pain specialists has accelerated, painspecialists and addiction medicine specialists now must collaborate to refineguidelines, help physicians identify the subpopulations that can be managed byprimary care providers, and discover safer strategies that may yield treatmentopportunities to larger numbers of patients.

Treating Patients with Addictive Disorders

Safe and effective pain treatment is especially important for persons with adrug use history because inadequate treatment or lack of treatment for pain may haveproblematic consequences, such as illicit drug use (e.g., heroin), misuse ofprescription opioids and other pain medications (e.g., benzodiazipines), psychiatricdistress, functional impairment and a tendency for health providers to attributepain complaints and requests for pain medication to an addictive disorder ratherthan to a pain disorder (Gureje, et al.,2001; ). Undertreatment of pain among addicted persons may leadto the adverse medical, social and personal consequences associated with continueddrug-seeking behavior (Savage, 1996). Paincomplaints may be most problematic among persons with opioid addiction, as thisgroup may have lower tolerance for pain than other addicted populations (Compton, 1994; ). Pain and opioid addictionmay be further intertwined among persons who have a history of abusing controlledopioid pain medications, such as oxycodone or hydrocodone.

A Possible Role on the use of Buprenorphine for the Treatment of ChronicPain

Increasing interest in developing clinical protocols for opioid treatment ofchronic pain in the population with substance abuse histories has highlighted therole of opioid medications that may have lower abuse potential. One medication thatis beginning to be examined is buprenorphine, a partial opioid mu agonist that iswell recognized as an analgesic (). In 2002, a sublingual tablet (both in mono form– Subutex® - and combined with naloxone - Suboxone®) wasapproved by the U.S Food and Drug Administration as a Schedule III medication forthe treatment of opioid dependence. In numerous controlled clinical trials, it hasbeen demonstrated to be highly efficacious in reducing illicit opioid use andpromoting treatment retention among opioid abusers (e.g., ; Kakko, Svanborg, Kreek, Heilig, 2003; O'Connor et al., 1998; Fudala et al., 2003). In opioid addicts, it suppresses the craving andwithdrawal symptoms associated with opioid use and also blocks the euphoric effectsof subsequent opioid use (See for a review).

As a partial mu-agonist, buprenorphine has a ceiling effect on its agonistactivity (Lewis, 1985; ). It is lesslikely than a full agonist to cause respiratory depression in opioid-naïvepatients (). This property of buprenorphine increases its safety profile byreducing the risk of accidental overdose (). The partial agonism ofbuprenorphine would presumably yield a ceiling effect for analgesia as well, whichwould limit the clinical use of the drug in pain management, but there is somequestion about the extent of this ceiling effect in practice (Dahan, et al., 2006).

Although the combination buprenorphine/naloxone tablet (Suboxone) mayprecipitate withdrawal in opioid-tolerant persons if it is injected, making itrelatively unattractive for diversion (CSAT,2004), there is nevertheless evidence of diversion, as would be expectedwith any psychoactive drug that has hedonic properties (; ). Rates of abuseare relatively low compared to full mu agonists and buprenorphine rarely is endorsedas a primary drug of abuse (; Rosenblum etal., 2007; SAMHSA, 2006).

In Europe, a transdermal formulation of buprenorphine has been approved forthe treatment of chronic pain (e.g., ; Sittl,2005). In post-marketing surveillance studies and in a multicenterrandomized controlled clinical trial, the transdermal patches were reported to beeffective and well-tolerated in the treatment of cancer and non-cancer chronic pain(Griessinger et al., 2005; Sittl, 2005; Sorge and Stittl, 2004; ). A transdermal formulation of buprenorphine isnot presently available in the United States.

The off-label use of sublingual buprenorphine tablets to treat chronic painhas been described in two clinical reports, one describing its use in a series ofchronic pain patients who were responding poorly to other opioid analgesics (Malinoff et al., 2005) and the other describingthe response of patients with both pain and addiction (). In both of these reports, theauthors reported that their patients were successfully treated with buprenorphine,e.g., pain relief and improved mood and functioning.

In a similar manner, two earlier publications describe the open-label use ofthe parenteral formulation of buprenorphine administered sublingually to treatpatients with chronic pain (; ). Although most patients were followed upfor less than one month, both studies reported good analgesia and low incidence ortime-limited unwanted side effects. There is also evidence from several preclinicalstudies and one study with human subjects that, in contrast to pure mu-agonists,buprenorphine exerts a lasting anti-hyperalgesic effect (Hans, 2007; Koppert, et al.,2005). The transdermal trials conducted in Europe, the anecdotal reportsof sublingual administration in North America, and buprenorphine’scomparatively high safety profile suggest that it would be valuable tosystematically study buprenorphine as a treatment of pain in patients with substanceuse disorders.

Conclusion

Opioids are among the most effective medications for moderate to severepain. Although there is a consensus on their utility as a treatment for chroniccancer pain, their long-term use for chronic non-malignant pain remainscontroversial. Several medical professional organizations acknowledge the utility ofopioid therapy and many case series and large surveys report satisfactory reductionsin pain, improvement in function and minimal risk of addiction. However, theclinical trials that have been conducted do not provide adequate evidence oflong-term effectiveness. Despite the consensus of pain specialists, and theeminently ethical and medically justified commentaries to consider opioid therapy inthe armamentarium of treatments for moderate to severe pain (), there is concern thatthe pendulum has swung from undertreatment to overtreatment (). This controversy is enhanced bythe increased prevalence of prescription opioid abuse, which has developedconcomitantly with an increase in opioid administration in the clinic. Theresolution of this controversy will require much more research and the acceptance oftreatment guidelines that recognize the dual obligations of the prescriber: tooptimize the balance between analgesia and side effects, and promote other favorableoutcomes, while concurrently assessing and managing the risks associated with abuse,addiction and diversion. At this juncture, it is important that the opioid treatmentdebate evolve from a discussion focused on “too little” or“too much” to one focused on identification and training of besttreatment practices. Improvement in opioid therapy can occur through research andtraining to aid practitioners to determine the appropriate patient subpopulationsand treatment protocols to achieve satisfactory outcomes.

Finally, it is imperative to advance a research agenda that leads to theidentification of methods that would enhance pain relief while reducing thelikelihood of addiction and other adverse events when opioids are selected fortherapy. This should include the testing of novel medications that may be safer ormore differentially effective for select treatment populations (as the proposal totest buprenorphine with high risk patients, discussed above) and the evaluation oftreatment protocols incorporating risk management techniques.

Acknowledgments

The authors wish to thank two anonymous reviewers who provided extremelythoughtful and helpful comments on an earlier version of this paper.Acknowledgement: Development of this paper was partially supported by a NationalInstitute on Drug Abuse grant R21 DA022675.

References