Publications
APS Bulletin • Volume 12, Number 1, January/February 2002
Pain and Public Policy
Corey D. Fox, PhD, Department Editor
Chronic Opioid Therapy: Another Reappraisal
R. Norman Harden, MD
Department Editor’s Note: Pain management practice suffers from no more controversial issue than the use of opioids in the treatment of chronic benign pain problems. Expansion of this practice in recent years has garnered the acute attention of the public, policy makers, state regulatory bodies, and payers. Dr. Harden has incisively reviewed the current state of practice and science in this area, one in which the former has clearly outpaced the latter. Chronic opioid therapy is evolving into “standard practice,” despite the dearth of rigorous evaluation. Moreover, little attention has been given to generating unbiased research funding, development of scientific or professional consensus on treatment goals or assessment, or operationally defining the relevant clinical syndromes. Despite exhortations to explore treatment alternatives (e.g., the American Academy of Pain Medicine/American Pain Society policy statement on the use of opioids), it has often been easier to prescribe opioids than to deal effectively with the complexities of chronic pain problems or embrace an appropriate advocacy role vis-à-vis insurers reluctant to support more comprehensive care. And all too often the palliation associated with chronic opioid usage has been reinforcing for the patient and physician. It is little wonder that the public microscope has become focused on this practice, and payers are also now beginning to pay attention. Some insurers are questioning the cost and value of chronic opioid usage; and a few workers’ compensation carriers are now examining the role of such practice in the extension of disability durations and costs. Notice should be taken. We hope this stimulates further debate, which can only enhance the practice of pain management.
The honeymoon is over
The overuse of opioids for any and all pain by any and all practitioners is finally being challenged, and the pendulum has swung back to a more moderate position. Unfortunately, significant mortality and morbidity caused this shift. Of course this decade of opioid zealotry was preceded by an equally inappropriate century of nihilism (Wilson, 1997). A whole generation’s conscience rings with admonitions to “just say no,” and the impact of these liminal and subliminal messages was clearly felt by the medical profession. The first evidence of a shift toward liberalization of prescribing opioids was seen in the early 1990s in surveys about physician prescribing patterns (Turk, 1992; Turk, Brody, & Okifuji, 1994). Soon after this, discussions of the issue left the realm of scientific discourse and became highly politicized and emotionally charged. To put it mildly, the use of opioids in chronic, nonterminal conditions remains very controversial.
Derivatives of Papaver somniferum are undoubtedly powerful and effective analgesics that exploit ubiquitous endogenous pain inhibition systems (Reisine & Pasternak, 1996). It is essentially indisputable that opioids are effective in acute traumatic and postoperative conditions that are primarily nociceptive (Patt, 1996). Unrelieved pain can have multiple negative effects on these patients. It can significantly lower functional effectiveness, decrease immune function, and delay recovery from injury and surgery (Maier & Watkins, 1996; Melzack, 1990; Page, 1996). It is equally clear that humane and aggressive palliation of pain is appropriate in terminal conditions, particularly cancer (Foley, 1985). What remains at issue is whether these drugs are appropriate, can remain effective, and are commensurate with effective functional recovery and rehabilitation in chronic nonterminal conditions (Fordyce, 1991; Schug & Large, 1995; Sjogren, Thomsen, & Olsen, 2000; Turk, 1992; Turk & Brody, 1991). The need remains for quality, unbiased science to answer the basic questions surrounding these medications. Although a few good randomized and controlled studies are finally available (Arkinstall, Sandler, & Goughnor, 1995; Kjaersgaard-Andersen, et al., 1990; Kupers, Konings, Adriaenen, & Gybels, 1991; Moulin, Iezzi, Amireh, Sharpe, Boyde, & Merskey, 1996; Roth, et al., 2000), no studies have been published that are of sufficient length to be clinically relevant to the question of long-term and perhaps lifetime therapy. What comprises appropriate research outcomes primarily reflects the bias of study designers as to what is most valuable in the treatment of pain. Rehabilitation-focused clinicians tend to emphasize functional objective outcomes (Becker, Sjogren, Bech, Olsen, & Eriksen, 2000; Fordyce, 1991; Turk, 1992), whereas other specialists may tend toward more subjective, palliative outcomes (Portenoy, 1991a; Portenoy & Foley, 1986; Turk; Zenz, Strumpf, & Tryba, 1992). The crux of the controversy may be this apparent dichotomy between palliation and rehabilitation, although this dichotomy may be more philosophical than real.
Efficacy
Opioids are clearly not a panacea; some studies would indicate a lack of response in up to 38% of patients, even with liberal use (Becker et al., 2000; Portenoy & Foley, 1986; Zenz et al., 1992). One factor that may determine the efficacy of chronic opioids is the generator of the pain, specifically whether it is predominantly neuropathic or nociceptive (Amer & Meyerson, 1987; Fields, 1988; Kupers et al., 1991; Portenoy, Foley, & Inturrisi, 1990). The animal literature provides persuasive evidence that opioids have little or no effect in certain neuropathic models (Kupers & Gybels, 1995; Puke & Wiesenfeld-Hallin, 1993; Xu, Hao, Aldskogius, Seiger, & Wiesenfeld-Hallin, 1992; Yamamoto & Mizuguchi, 1991), although there are exceptions (Neil, Kayser, Shen, & Guilbaud, 1990). There also is compelling evidence from human clinical research suggesting that opioids are less effective in neuropathic conditions (Amer & Meyerson; Bowsher, 1991; Kupers et al.; Max, Schafer, Culnane, Dubner, & Gracely, 1988; Patt, 1996; Portenoy et al.). Unfortunately, most clinical studies fail to specifically differentiate between types of pain (Fields) and lump a variety of painful conditions together (Arkinstall et al., 1995; Backonja & Foley, 1996; Moulin et al., 1996; Portenoy & Foley). There is an ongoing and critical need for more specific inclusion criteria as to the pain mechanism in studies such as these to determine whether the differential effect between neuropathic and nociceptive pain is real or an artifact of design (Harden, et al., 1999). Even with more clearly defined clinical neuropathic states widely divergent results with opioid therapy can occur (Eide, Jorum, Stubhaug, Bremnes, & Breivik, 1994; Kjaersgaard-Andersen et al., 1990; Max et al.; Rowbotham, Reisner-Keller, & Fields, 1991). There is some evidence that opioids may actually make certain pain states worse by causing hyperalgesia (Christensen & Kayser, 2000; Doverty, White, Somogyi, Bochner, Ali, & Ling, 2001; Mayer, Mao, Holt, & Price, 1999).
Dependency, addiction, and abuse
To confuse the recreational/street abuse of drugs of any type with the private clinical decision between a doctor and patient to use these drugs for an appropriate medical indication is a serious error. To date, there are no studies of adequate quality or sufficient power to arrive at conclusions about the incidence and prevalence of psychologic dependency, addiction, and abuse in the chronic, noncancer pain population (Fishbain, Rosomoff, & Rosomoff, 1992). The lack of a uniform terminology has long hampered research in this area (Fishbain et al.; WHO Expert Committee on Drugs Liable to Produce Addiction, 1952), and a Tower of Babel across clinicians, patients, public policy makers, and the media has evolved. The terminology for physical dependency, addiction, and pseudoaddiction has recently been somewhat clarified by a consensus group and was approved by the American Pain Society Board of Directors (American Academy of Pain Medicine, American Pain Society, & American Society of Addiction Medicine, 2001). Notably absent from this effort was a definition of psychological dependency, which is salient consideration in studying and clinically managing patients on opioids. Psychological dependency, defined as an emotional state of craving for a drug for its euphorigenic effects or to avoid negative effects associated with withdrawal, occurs at variable rates dependent on specific characteristics of the clinical situation (Fordyce, 1991, 1992; Rinaldi, Steindler, Wilford, & Goodwin, 1988). Psychologic dependency may in some cases be a consequence of fear of uncontrolled pain rather than a pursuit of euphoria or avoidance of abstinence (or pseudoaddiction) (Weissman & Haddox, 1989). True addiction, defined as the compulsive use of a substance resulting in physical, psychological, or social harm to the user and continued use despite that harm (Rinaldi et al.), is probably a rare phenomena in most chronic pain conditions. However, the presence of certain other psychiatric diagnoses (particularly personality disorders) and certain sociologic milieu may make abuse and addiction much more likely. The development of problems among those using opiate medications does not seem to be uniform across different types of pain and different situations. For instance recovering burn patients seem to be especially resistant to the development of problems with opioids (Perry & Hedrich, 1985). The key may be the environment, an opinion that is corroborated by the experience of opioid-addicted Vietnam veterans, most of whom, on returning to the United States, stopped abusing (Robins, Davis, & Nurco, 1974). Thus, numerous biopsychosocial factors must be carefully evaluated when determining risk of problems with chronic use.
Tolerance
The development of tolerance with chronic opioid use is one of the most contentious issues, and is central to the debate over the appropriateness of long-term opioid therapy (Jasinski, 1997). It is clear that tolerance develops to some degree in animal models (Basbaum, 1995; Yaksh, 1991), in cancer pain (Foley, 1985; Twycross, 1974), in acute pain (Chia, Liu, Wang, Kuo, & Ho, 1999), and in street use (Jasinski). It is reasonable to assume that tolerance may develop in all chronic dosing; however, the rate and extent of this tolerance and its true incidence has not been carefully assessed (Yaksh). In chronic pain management tolerance is a major issue, as dosage escalation (theoretically for the remainder of the patient’s natural life) is not a realistic possibility (Rayport, 1954). It is likely that human tolerance is approximately linear at first, but then plateaus at some dose. Unfortunately this plateau dose may be well above most physicians’ comfort level. Pain itself may influence the incidence and rate of tolerance development (Christensen & Kayser, 2000; Page, 1996; Portenoy, 1994a) and may act to reduce tolerance or dependency-producing properties of opioids (Christensen & Kayser; Mayer et al., 1999). Conversely, in some cases of persistent pain, there may be a change in the nociceptive process (for the worse) that causes an increased opioid requirement, mimicking tolerance (Backonja & Foley, 1996; Schug, Zech, Grond, Jung, Meuser, & Stobbe, 1992). In conducting opioid research it is critical to document potential progression of disease prior to attributing changes in dosage requirements to tolerance, although this may be extremely difficult in many of the nebulous diagnoses encountered in chronic pain management. Tolerance to opioid effects other than analgesia (e.g., respiratory depression, sedation, nausea, pruritus) develops at different rates and to different degrees (Cleary & Backonja, 1996; Portenoy, 1994a) and the rate at which tolerance develops to any effect may vary greatly between individuals (Fishbain et al., 1992; Portenoy, 1994b; Rinaldi et al., 1988).
Psychological contraindications
Some of the strongest arguments against chronic opioid therapy come from the neurobehavioral arena (Fordyce, 1992; Turner, Calsyn, Fordyce, & Ready, 1982), and psychiatric diagnoses are important factors to consider before initiating opioid therapy. Although it is clearly inappropriate to prescribe opiates to treat depression or anxiety, how do we make decisions on the use of opioids in pain syndromes in which these psychological phenomena are ubiquitous, and in some cases may represent the primary process? Opioids can worsen depression (Finlayson, Maruta, Morse, Swenson, & Martin, 1986; Maruta & Swanson, 1981; Rowbotham et al., 1991; Sjogren et al., 2000; Turner et al.), and opioid micro-withdrawal usually produces anxiety and irritability (Haertzen & Hooks, 1989). The argument that effective analgesia (using opioids) improves depression has never been proven (Rowbotham et al.; Twycross, 1974). In fact, in one well-designed study, no benefits regarding psychological functioning were shown with chronic opioid therapy (Moulin et al., 1996), and there are many studies suggesting that psychological functioning may worsen (Finlayson et al.; Maruta & Swanson; Portenoy et al., 1990; Rowbotham et al.; Sjogren et al.; Turner et al.). Psychological functioning in general has been shown to improve after opioid detoxification (Brodner & Taub, 1978; Rowbotham et al.). Pain patients have increased disease conviction, somatic preoccupation (Pilowsky, Chapman, & Bonica, 1977), and an externalized locus of control (Schug & Large, 1995), all of which may lead to increased opioid-seeking behaviors in the absence of increased nociceptive input. The nonanalgesic operant reinforcing effects of taking opioids (euphoria, anxiolysis, sense of well being) also may exacerbate opioid-seeking behavior (Jasinski, 1997). Patients’ families often complain that patients on chronic opioid therapy have changed and that they are more irritable and anger easily. Subtle changes in personality are very difficult to detect and have been variably supported by formal testing (Finlayson et al.; Haertzen & Hooks; Sjogren et al.).
Cognitive interference resulting from opioid use must be considered (Bruera, Macmillan, Hanson, & MacDonald, 1989; Sjogren et al., 2000). Significant cognitive impairment has been demonstrated in cancer patients (Bruera et al.) and in nonmalignant pain (Sjogren et al.), especially with significant dose increases. Continuous reaction times have proven slower (Banning & Sjogren, 1990; Sjogren & Banning, 1989). Methadone maintenance patients performed significantly poorer on a battery of learning and intermediate recall tests than abstinent addicts or controls (Gritz, et al., 1975). In another report, a type of organic brain syndrome was documented that may have been related to long-term opioids (Maruta, 1978). The evidence for cognitive problems is mixed, with other studies showing no measurable impact (Schnurr & MacDonald, 1995; Vainio, Ollila, Matikainen, Rosenberg, & Kalso, 1995; Chapman, 2001). It is likely that tolerance to most testable cognitive functions occurs, but the issue of cognitive impairment with rescue dose or dose increase is important.
Healthcare utilization
One of the presumed benefits of chronic opioid therapy is decreased utilization of healthcare resources. In fact, this is probably not the case: Patients on opioid therapy have significantly more hospitalizations (Turner et al., 1982), have significantly more surgeries (Jamison, Anderson, Peeters-Asdourian, & Ferrante, 1994; Portenoy, 1991b; Turner et al.), and spend more money on prescriptions (Turner et al.) than patients not taking opioids. Patients on opioids are often taking other dependency-producing medicines, especially benzodiazepines (Fishbain et al., 1992; Jamison et al.; Turner et al.). Although side effects and end organ toxicity are often blithely written off in the pro-opioid literature, this clearly is an area for serious consideration and must give the thoughtful physician pause. The side-effect profile of opioid therapy is well known and protean (Gritz et al., 1975; Jasinski, 1997; Kjaersgaard-Andersen et al., 1990; Milroy & Forrest, 2000; Stein, 1996). Effective strategies have evolved in the cancer pain arena to manage most of these (Twycross, 1974). Unfortunately, the use of other drugs is often required for the patient to be able to tolerate the side effects. The need for anticonstipation, antipruritic, and antisomnolence agents is widespread (Foley, 1985; Gonzales, Elliot, Portenoy, & Foley, 1991). Opioids may have negative interactions with these and other medications (Kreek, 1978). Significant alterations in respiratory, liver, endocrine, gastrointestinal, immune, nutritional, and motor functions have been noted (Kreek; Sylvester, Levitt, & Steen, 1995). Death occurs infrequently (Milroy & Forrest) but is currently a common topic in the lay literature. (See www.mapinc.org/find?186 for a summary of lay publications.) These side effects and the need for medications and medical interventions to manage them can lead to a seemingly endless spiral of healthcare costs.
Palliation versus rehabilitation
The essence of the chronic opioid controversy may stem from the divergent goals and philosophies of physicians. If the doctor’s primary goal is to palliate, chronic opioid therapy is an expedient way to achieve this goal. If the primary goal is to rehabilitate and restore the patient to optimal functioning, opioids may be contraindicated (Becker et al., 2000; Brodner & Taub, 1978; Rayport, 1954; Maruta & Swanson, 1981; Rowbotham et al., 1991; Turner et al., 1982). As an example the chronic use of opioids may place serious and perhaps insurmountable restrictions on vocational rehabilitation. As vocational rehabilitation is often an intrinsic goal of interdisciplinary care, an assessment of analgesic-induced performance deficits becomes important (Bradley & Nicholson, 1986; Payne, 1991). It is known that patients on opioids have a higher rate of unemployment than chronic pain patients using nonopioid therapies (Jamison et al., 1994). Whether this is due to increased pathology in opioid patients or decreased motivation from the opioids themselves is unknown. Driving ability has received much attention (Bradley & Nicholson; Chapman, 2001; Joranson & Gilson, 1997; Payne). Whether a physician can ethically and safely release a patient to drive, operate heavy machinery, or perform jobs requiring high levels of attention or decision making is a substantial issue (Bruera et al., 1989; Chapman, 2001; Payne; Vainio et al., 1995), especially after dosage increase or rescue dosing. Prescribing doctors must ask themselves if they feel comfortable having a patient on high-dose opioids driving their children’s school bus, or having a patient who recently took a rescue dose of an immediate-release drug operating the crane overhead, or even having the patient requiring a recent increase in dosage preparing their tax returns (Bradley & Nicholson; Payne). Even if the physician feels comfortable prescribing in these scenarios, should the employer be made aware of this? Questions of liability and insurability of such workers take on profound importance in our litigious society.
In the active rehabilitation process other opioid side effects can be problematic (Brodner & Taub, 1978; Maruta & Swanson, 1981; Rowbotham et al., 1991; Turner et al., 1982). The patient who is too somnolent to effectively perform physiotherapies or participate and integrate psychotherapeutic principles is wasting valuable healthcare dollars and time. Opioid users had significantly lower treatment success rates in one study (Maruta & Swanson, 1981) and after detoxification, patients performed better in rehabilitation (Brodner & Taub; Kupers & Gybels, 1995; Rowbotham et al.). This must be balanced with the fact that a certain level of analgesia may be necessary for a patient to effectively participate in rehabilitation (Arkinstall et al., 1995), though often this analgesia may be attained by nonopioid pharmacology or nerve blocks (Brodner & Taub; Rayport, 1954; Rowbotham et al.). In the rehabilitation context it may be necessary to use minor opioids as “rescue agents,” for instance, prior to a particularly painful session of physical therapy.
There should be little argument that the ultimate goals of rehabilitation (e.g., optimal functional recovery, decreased healthcare utilization, maximal self-actualization) are more valuable than simple long-term palliation (Stein, 1996). The long-term outcomes of interdisciplinary pain management techniques are so effective, and so many nonopioid drugs have been conclusively proven to help that these may obviate the need for chronic opioid therapy in many patients (Becker et al., 2000; Merskey, 1997; Rowbotham et al., 1991). However, because opioids are “easy” and represent a path of little resistance, they may prevent the patient (or the physician) from vesting in a difficult and uncomfortable rehabilitation course. A physician’s choice to palliate and not rehabilitate is a profound clinical, ethical, and medico-economic decision that must not be taken lightly or be based on unfounded dogma.
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R. Norman Harden is an associate professor, Department of Physical Medicine and Rehabilitation, Northwestern University Medical School; director, Center for Pain Studies, Rehabilitation Institute of Chicago; and Addison Chair in Pain Studies.