Opioids and the Treatment of Chronic Pain

Opioids and the Treatment of Chronic Pain: Controversies, Current Status, and Future Directions –  free full-text PMC article – Jul 2009

In most individuals, when opioids are taken to treat pain, there appears to be no overt effect from change in these systems. In some cases, however, powerful reinforcement occurs…

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 pain and suffering

This is a long post because the article contained so many gems of information (with references!).  

Nevertheless, despite the advances in pain medicine and the wider use of opioids for various chronic pain conditions, there is still considerable controversy surrounding the type of conditions that should be treated, whether the treatment can be generally safe and effective in selected patients, and what the clinical goals should be.


Opioids have been regarded for millennia as among the most effective drugs for the treatment of pain.

Their use in the management of acute severe pain and chronic pain related to advanced medical illness is considered the standard of care in most of the world.

In contrast, the long-term administration of an opioid for the treatment of chronic non-cancer pain continues to be controversial.

Concerns related to effectiveness, safety, and abuse liability have evolved over decades, sometimes driving a more restrictive perspective and sometimes leading to a greater willingness to endorse this treatment.

The past several decades in the United States have been characterized by attitudes that have shifted repeatedly in response to clinical and epidemiological observations, and events in the legal and regulatory communities.

The interface between the legitimate medical use of opioids to provide analgesia and the phenomena associated with abuse and addiction continues to challenge the clinical community, leading to uncertainly about the appropriate role of these drugs in the treatment of pain.

This narrative review briefly describes the neurobiology of opioids and then focuses on the complex issues at this interface between analgesia and abuse, including terminology, clinical challenges, and the potential for new agents, such as buprenorphine, to influence practice.

History of Opioids

Developments in the 19th century transformed the practice of medicine and initiated the tension between the desire to make available the medicinal benefits of these drugs and recognition that the development of abuse and addiction can lead to devastating consequences for individuals and for society at large


Beginning in the twentieth century, there were many research advances and major changes in the way opioids were used for the treatment of pain and addiction

These included attempts among several nations and international organizations to control the distribution and use of opioids

the introduction of opioid maintenance therapy for the treatment of opioid addiction (first with morphine and later with methadone, LAAM (levo-alpha acetyl methadol) and sublingual buprenorphine), the discovery of the endogenous opioids, and the recognition that pain is a debilitating and destructive disease and that opioids are essential for the treatment of many forms of acute and chronic pain.

During most of the twentieth century, the widely held perception among professionals in the United States was that the long-term use of opioid therapy to treat chronic pain was contraindicated by the risk of addiction, increased disability and lack of efficacy over time.

During the 1990’s, a major change occurred, driven by a variety of medical and nonmedical factors (see below). The use of opioids for chronic pain began to increase, showing a substantial year-to-year rise that continues today.

This increased use of opioids for legitimate medical purposes has been accompanied by a substantial increase in the prevalence of nonmedical use of prescription opioids

This link between increased medical use and increased abuse has driven 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 barriers on the legitimate use of opioid medications, acknowledging both that increased abuse is probably inevitable when a psychoactive drug becomes more accessible and that attempts to control abuse can have the unintentional effects of discouraging treatment 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 opiate receptors.

Conventionally, the term opiate can be used to describe those opioids that are alkaloids, derived from the opium poppy; these include morphine and codeine.

Opioids include semi-synthetic opiates, i.e., drugs that are synthesized from naturally occurring opiates (such as heroin from morphine and oxycodone from thebaine), as well as synthetic opioids such as methadone, fentanyl, and propoxyphene.

The term narcotic is a legal designation and should not be used in the clinical setting; it refers to opioids and a few other drugs 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 are usually administered for pain in the ambulatory setting.

These include combination products,

  • such as those containing hydrocodone and acetaminophen (Vicodin®, Lorset®)
  • or ibuprofen (Vicoprofen®),
  • tramadol and acetaminophen (Ultracet®),
  • oxycodone and acetaminophen or aspirin (Percocet® or Percodan®), and
  • those containing codeine and acetaminophen or aspirin.

The single 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 in both the central nervous system and the peripheral nervous system.

These receptors also bind endogenous opioid peptides (endorphins), which are involved in pain modulation and numerous other functions in the body. Among these functions are those mediated by deep structures of the brain, which are involved in the modulation of reinforcement and reward mechanisms, mood and stress

When an opioid given for pain binds to receptors, analgesia may be accompanied by any of a diverse array of side effects related to the activation of receptors involved in other functions.

In most individuals, when opioids are taken to treat pain, there appears to be no overt effect from change in these systems. In some cases, however, powerful reinforcement occurs, expressed as efforts to repeat the administration and these reinforcing outcomes may be associated with craving and with positive mood effects such as euphorigenic or pleasurable effects

These outcomes, which are uncommon but potentially serious when they occur (driving the development of an addictive pattern of use), can occur in the presence or absence of pain.

Although these effects could be associated with iatrogenic addiction, they appear to be rare in patients who do not have risk factors suggesting the existence of the biological substrate for opioid-induced craving (see below).

Although several types of opioid receptors exist (e.g., mu, kappa and delta), opioid drugs largely produce their analgesic and reinforcing effects via activation of the mu opioid receptor; thus, opioids used for pain are often described as, “mu agonists”.

Mu drugs that have the ability to fully activate opioid receptors (e.g., higher doses produce greater receptor activation in a 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 not activate, receptors are referred to as opioid antagonists (e.g., naltrexone, naloxone); they can reverse the effects of mu opioid agonists

Brief Overview of Chronic Pain

Chronic pain is a highly complex phenomenon, which may or may not be primarily driven by tissue injury.

Conventionally, the most common forms of chronic pain are divided into those labeled “nociceptive”, or pain caused by ongoing stimulation of pain receptors by tissue damage, and those labeled “neuropathic”, or pain presumed to be related to damage to or dysfunction of the peripheral or central nervous system.

These categories of pain simplify a complex reality in which both acute and chronic pain are induced by multiple peripheral and central mechanisms, which continually interact with each other and with numerous pain modulating systems. The perturbations that ultimately results in pain perception are caused by neurophysiological processes and other related systems.

For example, recent evidence has begun to highlight the role of neuroimmune activation following a tissue injury as an important mechanism in the development of chronic pain (DeLeo, 2006).

The role of cytokines and other inflammatory mediators is obvious in inflammatory nociceptive pains, such as some types of arthritis, but new data suggest an equally salient role in the development of chronic neuropathic pain associated with central sensitization of neural pathways following peripheral injury.

All chronic pain is profoundly influenced by psychological processing and responses).

Pain severity and pain-related functional impairment are often found to be associated with psychological and social factors, and patients with identical diseases associated with pain, such as degenerative disk disease, may vary greatly in their reports of pain severity and pain behaviors. There is an extensive literature documenting the importance of operant conditioning factors and cognitive-behavioral factors in the maintenance of chronic pain behaviors

The contribution of psychological, social and psychiatric factors should not lead to the conclusion that a pain syndrome is primarily psychogenic. Pain related exclusively or primarily to psychological factors occurs, but is far less prevalent than pain associated with organic processes that are powerfully influenced by psychosocial mediators and psychiatric comorbidities.

The “pattern of suffering” or the pain-related disability that often occurs in concert with persistent pain commonly touches on all domains of function. Patients with chronic pain may demonstrate pain-related interference with ability to perform usual activities at home, work, or school; maladaptive or dysfunctional behaviors, social isolation, and poor sleep patterns; and frequent health care utilization .

Further recognition of the increased interest in the assessment and management of pain is underscored by the U.S. Federal Law (Pain Relief Promotion Act of 2000) that declared the first decade of the 21st century as the Decade of Pain Control and Research.

Chronic pain is a major public health problem, which is associated with devastating consequences to patients and families, a high rate of health care utilization, and huge society costs related to lost work productivity. The existing treatments for chronic pain are unable to address the problem and better therapies are urgently needed. The need for these therapies is the backdrop for the expanding use of opioid drugs. An extensive clinical experience indicates that long-term opioid therapy is able to help selected patients have a better quality of life, less use of health care, and improved productivity. The medical community is no longer debating the reality of these outcomes, but rather, is now focused on a more fruitful debate about patient selection and the benefits and burdens of these drugs in varied subpopulations. Whether the frame of reference is the individual patient and family, or society-at-large, the issue is about balancing the potential benefits of these drugs in the large and diverse population with chronic pain with its potential risks.

Terminology of Opioid Abuse: Dependence, Tolerance, Addiction

According to the consensus document, tolerance is defined as a decreased subjective and objective effect of the same amount of opioids used over time, which concomitantly requires an increasing amount of the drug to achieve the same effect. Although tolerance to most of the side effects of opioids (e.g., respiratory depression, sedation, nausea) does appear to occur routinely, there is less evidence for clinically significant tolerance to opioids– analgesic effects.

For example, there are numerous studies that have demonstrated stable opioid dosing for the treatment of chronic pain and methadone maintenance for the treatment of opioid dependence (addiction) for extended periods..

some patients will experience worsening of their pain in the face of dose escalation. It has been speculated that some of these patients are not experiencing more pain because of changes related to nociception (e.g. progression of a tissue-injuring process), but rather, may be manifesting an increase in pain as a result of the opioid-induced neurophysiological changes associated with central sensitization of neurons that have been demonstrated in preclinical models and designated opioid-induced hyperalgesia.

Analgesic tolerance and opioid-induced hyperalgesia are related phenomena, and just as the clinical impact of tolerance remains uncertain in most situations, the extent to which opioid-induced hyperalgesia is the cause of refractory or progressive pain remains to be more fully investigated

Physical dependence represents a characteristic set of signs and symptoms (opioid withdrawal) that occur with the abrupt cessation of an opioid (or rapid dose reduction

Unlike tolerance and physical dependence which appear to be predictable time-limited drug effects, addiction is a chronic disease that “represents an idiosyncratic adverse reaction in biologically and psychosocially vulnerable individuals”.

The distinction between
physical dependence and addiction
is not always made clear in the pain literature.

Most patients who are administered opioids for chronic pain behave differently from patients who abuse opioids and do not ever demonstrate behaviors consistent with craving, loss of control or compulsive use

Of course, pain and addiction are not mutually exclusive and some patients who are treated for pain do develop severe behavioral disturbances indicative of a comorbid addictive disorder.

Some patients who are treated with opioids for pain display problematic behaviors that, on careful assessment, do not reflect addiction, but rather, appear to relate to a different process.

In addition, there appear to be some patients who engage in problematic behaviors related specifically to desperation about unrelieved pain. The term pseudoaddiction was coined to describe the latter phenomenon

The term aberrant drug-related behaviors has been used to indicate the broad array of problematic nonadherence behaviors, the nature of which is uncertain until a diagnosis can be developed based on astute clinical assessment.

Distinction between Withdrawal and Chronic Pain

Because addiction is associated with psychological distress and physical discomfort in the form of opioid withdrawal symptoms, it may be difficult to distinguish primary chronic pain complaints from withdrawal pain.

Withdrawal also may have the potential to increase baseline pain related to other processes. For example, based on anecdotal evidence from chronic pain patients, withdrawal from opioids can greatly increase pain in the original pain site.

These phenomena notwithstanding, there also is evidence that experienced drug abusers are able to distinguish withdrawal pain from chronic pain. 

Chronic pain is typically localized (e.g., back pain, headache) and persists (although with varying degrees of severity) for long periods of time

Withdrawal from short-acting opioids, such as heroin, is typically short-lived; physical symptoms are likely to reach their maximum intensity over a 36–72 hour period and to reduce in intensity after that

Opioid Treatment for Chronic Pain

Opioid therapy is the mainstay approach for the treatment of moderate to severe pain associated with cancer or other serious medical illnesses

the use of opioids remains controversial due to concerns about side effects, long-term efficacy, functional outcomes, and the potential for drug abuse and addiction

Other concerns that may contribute to the hesitancy to prescribe opioids may be related to perceived and real risks associated with regulatory and legal scrutiny during the prescribing of controlled substances

Narrative reports on the use of opioids for CNMP have underscored the effectiveness of opioid therapy for selected populations of patients and there continues to be a consensus among pain specialists that some patients with CNMP can benefit greatly from long-term therap

This consensus, however, has received little support in the literature. Systematic reviews on the use of opioids for diverse CNMP disorders report only modest evidence for the efficacy of this treatment

A meta-analysis of 41 randomized trials involving 6,019 patients found reductions in pain severity and improvement in functional outcomes when opioids were compared with placebo.

Among the 8 studies that compared opioids with non-opioid pain medication, the six studies that included so-called “weak” opioids (e.g., codeine, tramadol) did not demonstrate efficacy, while the two that included the so-called “strong” opioids (morphine, oxycodone) were associated with significant decreases in pain severity

The standardized mean difference (SMD) between opioid and comparison groups, although statistically significant, 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 for CNMP leads to reductions in pain severity, although evidence for increase in function is absent or less robust

Little or no support for the efficacy of opioid treatment was reported in two systematic reviews of chronic back pain

Adding further to the controversy over the utility of opioid analgesics for CNMP is the absence of epidemiological evidence that an increase in the medical use of opioids has resulted in a lower prevalence of chronic pain.

Although this epidemiological study may be interpreted as demonstrating that opioid treatment for CNMP has little benefit, the authors acknowledge that these disquieting findings do not indicate causality and could be influenced by the possibility of widespread undertreatment, leading to poorly managed pain

It is generally acknowledged that there is a wide degree of variance in the prescribing patterns of opioids for chronic pain

A substantial number of physicians are reluctant or unwilling to prescribe long-acting opioids to treat CNMP, even when it may be medically appropriate

Controversy about the long-term effectiveness of opioid treatment also has focused on the potential clinical implications of opioid-induced hyperalgesia. As noted earlier, exposure to opioids can result in an increased sensitivity to noxious stimuli in animals, and an increased perception of some types of experimental pain in humans

The extent to which this phenomenon is relevant to the long-term opioid therapy administered to most patients with chronic pain is unknown. Although experimental evidence suggests that opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain, there have been no reports of observations in the clinical literature to suggest that it should be a prominent problem.

Outcome studies of long term use of opioids are compromised by methodological limitations which make it difficult to acquire evidence of efficacy

Methodological limitations may be unavoidable because of the ethical and practical challenges associated rigorous studies such as randomized controlled trials.

Guidelines for opioid therapy must now be based on limited evidence; future evidence may be acquired by utilizing other study designs such as practical clinical trials. 

recent guidelines have emphasized the need to initiate, structure and monitor therapy 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

The relatively recent recognition that guidelines for the opioid treatment of chronic pain must incorporate both the principles of prescribing as well as approaches to risk assessment and management may represent an important turning point for this approach to pain management

pain specialists and addiction medicine specialists now must collaborate to refine guidelines, help physicians identify the subpopulations that can be managed by primary care providers, and discover safer strategies that may yield treatment opportunities to larger numbers of patients.



Opioids are among the most effective medications for moderate to severe pain.

Despite the consensus of pain specialists, and the eminently ethical and medically justified commentaries to consider opioid therapy in the armamentarium of treatments for moderate to severe pain

there is concern that the pendulum has swung from undertreatment to overtreatment

The resolution of this controversy will require much more research and the acceptance of treatment guidelines that recognize the dual obligations of the prescriber: to optimize the balance between analgesia and side effects, and promote other favorable outcomes, while concurrently assessing and managing the risks associated with abuse, addiction and diversion.

At this juncture, it is important that the opioid treatment debate evolve from a discussion focused on “too little” or “too much” to one focused on identification and training of best treatment practices.

Finally, it is imperative to advance a research agenda that leads to the identification of methods that would enhance pain relief while reducing the likelihood of addiction and other adverse events when opioids are selected for therapy

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