Pain, Opiates, and Addiction

Introduction

Prescribing of opiates for the control of cancer pain and pain of neuropathic origin has often been inadequate for reasons that include lack of education on pain management, restrictive drug control laws, and the fear of addiction ( ). Opiate addiction is distinguished by compulsive use of opiates to the detriment of the user’s physical and psychological health and is often now referred to as a chronic relapsing disease that predisposes a recovered addict to relapse many years after the last drug experience. Pseudo-addiction may also occur following inadequate prescribing of opiates to control pain, and although the patient may exhibit signs of compulsive drug seeking and hoarding of drugs, they disappear when the pain has been brought under control. Addiction is not defined by dependence, which refers to the acute manifestation of withdrawal signs following the termination of drug treatment. Opiate addiction is also not defined by the appearance of opiate tolerance, which describes the gradual loss of efficacy of the drug over time and therefore the necessity of increasing opiate doses to maintain the same level of analgesia.

Confusion abounds among clinicians with respect to the risk for opioid addiction in pain relief, partly because of a lack of training and partly because of confusing terminology ( ). This confusion and clinical uncertainty are manifested most acutely in the treatment of chronic non-cancer pain. Medical prescription of opioids has been and will continue to be closely controlled and regulated to avoid drug diversion, misuse, and inappropriate prescribing. In the United States, the Harrison Narcotic Act (1914) resulted in numerous prosecutions of physicians prescribing opioids. This led to the prevailing dictum to “stay away from addicts,” which evolved into “stay away from opioids” and has resulted over years in a lack in understanding of opioid addiction as distinct from therapeutic use of opioids for pain relief. Although legislation has evolved, opioids remain stringently regulated and may contribute to the “opiophobia” seen in many countries and sustain the belief that all consumption of opioids leads to addiction. Regulations may impede access to controlled drugs, leave opioid-sensitive pain untreated, and in some cases, fuel the purchase of illegal, controlled drugs ( ).

In the United States, investigation, fear of inappropriate scrutiny, and the perceived personal risk in prescribing opioids influence prescription patterns to a greater extent than rapidly changing conventional and evidence-based practice would warrant. For many of these reasons, prescribing of opiates for the control of cancer pain and pain of neuropathic origin has often been inadequate and less than optimal. Unwanted side effects of opioid treatment are numerous and include nausea, constipation, sedation, confusion, altered libido, weight gain, and respiratory depression. Dependence can be both physical and psychological (although these terms are not to be confused with addiction):

• Physical dependence is defined by the abstinence syndrome (withdrawal) and includes abdominal cramps, diarrhea, vomiting, restlessness, pupil dilatation, sweating, and dysphoria.

• Psychological dependence refers to the need and beliefs of patients in pain that opioids are necessary to reduce the pain.

Dependence and addiction are terms that are unfortunately often used interchangeably, with the compulsive drug seeking, craving, and potential for relapse, characteristics that are always associated with addiction, essentially being ignored. has suggested that in the clinical setting, addiction should be defined as a psychological and behavioral syndrome characterized by loss of control and continuing compulsive drug use despite harm ( Box 26-1 ).

Evidence of Tolerance and Dependence with Chronic Opioid Treatment

Evidence of the Analgesic Efficacy of Opiates Without Addiction

Numerous studies over the past 4 decades have reported on the use of opioids for non-cancer pain. Many have been too short (1–2 weeks) to be of relevance to long-term therapy. However, even these studies largely support evidence of the efficacy, lack of tolerance, and lack of misuse of opioids. Studies from the 1980s were not optimistic and reported less favorable outcomes, with opioid misuse, heightened pain, and a poor response to treatment in patients with chronic pain, all within a setting of multidisciplinary pain teams and extended pain treatment programs ( ; ; ). However, longer-term studies are increasingly supporting the evidence for efficacy without tolerance or increased abuse. systematically reviewed 13 randomized, placebo-controlled trials of opioids (either oral or intravenous) for chronic non-cancer neuropathic or musculoskeletal pain, and the findings suggested a significant reduction in pain in both groups (reported as a reduction in pain intensity). In another study in a single-university outpatient setting, sickle cell patients were offered liberal access to opioids modeled on cancer pain treatment. Over a 2-year follow-up period, there was a decline in emergency attendance for analgesia (by 67%) and reduced hospital admissions (by 44%), and no opioid abuse was reported ( ). In a more recent study of Danish patients receiving a variety of opiates for non-cancer chronic pain, opioid use was associated with poor quality of life and functional disturbance ( ), although the obvious conclusion that opioid treatment has little benefit has been disputed ( ). Nevertheless, in a recent clinical update for the International Association for the Study of Pain (IASP), cites the largely unknown value of opioid treatment in patients with chronic non-cancer pain as one of the major crises in pain management.

Despite the evidence that patients can be treated with opioids for long periods without becoming addicted, there has been a pervasive increase in the abuse of prescription opioids ( ). The majority of patients who were referred to one drug rehabilitation service for prescription opioids had psychological co-morbidity, risk-taking behavior, and a history of past abuse ( ). Oxycodone, an alkaloid of morphine that has recently (since 1996) been repackaged and marketed for pain relief, has been the focus of reports suggesting that the drug has led to addiction, abuse, and more than 100 deaths in the United States. Like all opioids, there is a risk for addictive behavior, but there is no indication that oxycodone is any more addictive than other opioids. However, the rapid rise in addiction in the United States may in part be explained by the properties of controlled-release oxycodone, which can be crushed and dissolved in water, thereby destroying its controlled-release properties and allowing ingestion (transmucosally or intravenously) to deliver a rapid high. In addition, sales of prescription opioids in the United States increased four-fold from 1999–2010; they exceeded $8 billion ( ) and the number of prescriptions exceeded 201.9 million ( ), with an increase of almost 50% between 2000 and 2009 ( ), which has led to widespread and cheap availability. The main areas reporting addiction to prescribed oxycodone also reported a high incidence of co-morbid features predictive of addiction, including high rates of work-related injury, poverty, and isolation ( ).

A review of the increase in abuse of five prescribed opioids (fentanyl, hydromorphone, meperidine, morphine, and oxycodone) between 1996 and 2002 reported that all except meperidine exhibited an increase in medical use by more than 70% (morphine, 73%; oxycodone, 402%), with a corresponding increase in abuse. Fentanyl was noted to have the largest increase in abuse (646%), followed by oxycodone (346%) and morphine (113%). However, abuse of prescribed opioids still accounted for less than 10% of all abuse mentions. Theft, prescription diversion, and multiple prescribers were the predominant source of prescribed opioids ( ).

Thus, although all opioids can be abused, oxycodone per se appears to be no more or no less addictive than other preparations. The availability and ease of conversion from controlled to immediate release and the huge press interest have increased knowledge and abuse of oxycodone. Awareness of guidelines and appropriate selection of patient groups are important to limit abuse and diversion ( ).

In opioid-dependent (methadone-maintained) people, pain can and does co-exist in the face of high levels of exogenous opioids. In these patients it has been suggested that there is analgesic tolerance to methadone and that pain should be treated according to the same principles as used for non–opioid-dependent patients ( ). Little evidence is available on rates of re-emergence of true addiction in this group of patients, and a common protocol is to maintain the methadone regimen and to treat the pain with a separate opioid.

The Neurobiology of Addiction

Thus, from a relatively small number of studies, sometimes with conflicting results, it may be concluded that there is a population of chronic pain patients in whom opioids may be used successfully to achieve pain relief without risk for misuse and toxicity. Nevertheless, there may also be a population in whom opioids are ineffective in relieving pain or who display signs of toxicity, dependence, or aberrant drug-related behavior ( ). However, although the occasional development of opiate addiction in pain patients may well be the exception to the rule that ongoing pain generally blunts the development of addiction, how the transition to addiction occurs at a neurobiological level is unclear.

Opiates and all potential drugs of abuse are thought to act on the reward “centers” within the brain—in reality, an interconnected matrix of neural structures that modulate the motivational state of the animal. The analgesic actions of opiates also work through an extensive network of brain and spinal circuits, and to a large extent (but not entirely) these networks overlap with those that control motivational states. This suggests that the reward potential and analgesic potency are related by the affective state induced by opiates, which is indeed often described as a sense of well-being and indifference to ongoing pain ( ). Addictive drugs are thought to highjack neural systems that evolved to mediate behavior normally directed toward natural rewards such as food, water, and sex. Yet the shift from working for a drug reward to the compulsive searching and craving for drugs characterized by addiction has as yet little neurobiological explanation. Indeed, many individuals will be exposed to addictive drugs yet few will become addicted. estimated that less than 0.01% of hospitalized patients passively receiving chronic opiates are at subsequent risk for addiction.

The failure of opiate addiction to develop in individuals in an ongoing or relieved pain state, even with large doses of the drug, may present a novel opportunity to examine the transition to addiction in terms of the underlying neurobiological machinery.