Topics in Review: Use of opioids to treat chronic, noncancer pain

Journal List > West J Med > v.172(2); Feb 2000

West J Med. 2000 February; 172(2): 107–115.

PMCID: PMC1070769

Topics in Review

Use of opioids to treat chronic, noncancer pain

Barry D Dickinson,¹ Roy D Altman,¹ Nancy H Nielsen,¹ and Michael A Williams¹

¹ for the Council on Scientific Affairs, Council on Scientific Affairs, American Medical Association, 515 N State Street, Chicago, IL 60610

Correspondence to: Dr Dickinson, barry_dickinson/at/ama-assn.org

The American Medical Association's Council on Scientific Affairs previously addressed barriers to the appropriate management of pain in patients with acute and chronic cancer pain (Report 4, presented at the annual meeting of the AMA, 1995). Authoritative guidelines on these aspects of pain management now exist.¹^,² However, the use of controlled substances to treat chronic pain in patients who do not have cancer continues to be at the forefront of regulatory, disciplinary, and clinical practice disputes.

A number of critical issues underlie physicians' concerns over the use of opioids in patients with chronic, noncancer pain. These issues include safety and efficacy, the development of tolerance and physical dependence, the potential for drug misuse or addiction, and physicians' fear of regulatory scrutiny and legal sanctions. These issues and the neurobiology of acute and chronic pain are briefly reviewed in this report.

Some physicians continue to undertreat pain. Some of this is influenced by the lack of adequate education and training in pain diagnosis and treatment, which contributes to poor management by physicians of chronic pain. Thus, improvements in education must accompany any initiatives designed to eliminate other barriers.

English-language reports of studies on people were selected from a MEDLINE search of the literature from 1966 to June 1999 using the MeSH headings “analgesics, opioid,” “pain,” and “chronic disease” but excluding “neoplasm.” A total of 257 articles were retrieved. Additional articles were identified by reviewing the references cited in these publications. Further information was obtained from the websites of the American Pain Society (www.ampainsoc.org), the American Academy of Pain Medicine (www.painmed.org), the American Academy of Pain Management (www.aapainmanage.org), the American Society of Addiction Medicine (www.asam.org), the Pain and Policy Studies Group (www.medsch.wisc.edu/painpolicy), and from recently published textbooks.

Summary points

Peripheral tissue or nerve damage may lead to long-term changes that cause persistent pain in the absence of ongoing stimulation
Opioids are effective in treating selected patients with chronic pain not related to cancer
Patients most likely to benefit from opioids are those whose pain has an identifiable cause
The risk of addiction is increased if a patient has a history of substance abuse but addiction seems to occur infrequently in other patients
Physicians' fears of regulatory scrutiny play a part in the undertreatment of pain

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. The perception of pain is influenced by physiological, psychological, and social factors. Thus, the distinction between pain (as the primary sensory experience arising from a noxious stimulus) and suffering (the human reaction to the sensory experience) is important. The human reaction (suffering) takes on an added dimension in patients who have chronic, noncancer pain. Some of these patients not only have persistent pain but also have overriding affective components and learned responses that can lead to severe psychosocial disability and a pattern of repeated interaction with the healthcare system.

Nociceptive pain

Pain is normally evoked by only those stimuli that are sufficiently intense to activate primary afferent A fibers and C-fiber nociceptors. These free nerve endings are located in skin, viscera, muscle, fascia, blood vessels, and joint capsules. There are many varieties of nociceptors, the most important of which are nociceptive afferents and polymodal afferents. Polymodal afferents respond to heat and mechanical stimuli; some also respond to chemical stimuli.

Peripheral sensitization and primary hyperalgesia

Tissue damage and inflammation cause peripheral sensitization of nociceptors. Sensitized nociceptors have lowered response thresholds. Therefore, they can be activated by a light touch and thermal stimuli that are normally not painful, and during movement. They also exhibit an increased response to stimuli that are normally painful (known as primary hyperalgesia).

In contrast to A fibers, whose postsynaptic potentials are on the order of milliseconds, C-fiber potentials last up to 20 seconds.³ Repetitive C-fiber input changes the excitability of spinal cord neurons. Stimulation at low frequencies causes a progressive prolongation in the response of certain dorsal horn neurons. Persistent stimulation causes central sensitization, which is characterized by an increased excitability of these neurons.⁴ Clinically, it manifests as pain sensitivity beyond the sites of tissue damage or inflammation (secondary hyperalgesia) and the ability of stimuli from low threshold A receptors (which normally mediate light touch and hair movement) to generate sensations of pain or tenderness (mechanical allodynia).⁵^,⁶ Thus, in the presence of central sensitization, pain can be signaled by large diameter afferents as well as by small diameter afferents. This process is believed to play a major role in neuropathic pain.

Neuropathic pain

Neuropathic pain results from abnormal operation of the nervous system after injury, usually injury to neural tissue. These types of pathophysiological pain are often chronic and differ qualitatively from acute nociceptive pain. Both peripheral and central changes contribute.

The pain system

The pain system is subject to ongoing modulation and modulation by injuries. The view that chronic pain is merely an extension of acute nociceptive pain is not valid, particularly in cases of neuropathic pain. With central sensitization, pain can also be signaled by low threshold mechanoreceptors. Ectopic discharges from injured neuronal elements, phenotypic switches, and gene expression also participate in sensory signaling and modulation of central excitability that may ultimately cause persistent pain in the absence of an ongoing stimulus.

The relief of suffering is universally acknowledged as a cardinal goal of the ethical and compassionate practice of medicine. Pain is a complex phenomenon for both the patient and caregiver, influenced by physiological and psychosocial factors. The challenges of clinical management are heightened by pain since it influences the interpersonal relationship between the patient and the physician. The obligation of physicians to relieve pain is a conditional obligation, in which the ethical principle of beneficence guides a physician's duty to relieve pain (unless a patient of sound mind rejects such treatment). The proffering of treatment and, in some instances the withdrawal of treatment, may relieve suffering and thereby promote good.

The physician also has an ethical obligation to promote the dignity and autonomy of all patients. Physicians must respect the decisions made by competent patients. It is ethically acceptable to administer drugs in whatever dose is necessary to relieve a patient's suffering, even if doing so may cause foreseeable side effects, as long as patients or their proxies are made aware of this possibility. However, physicians should not accede to demands for treatment that are inconsistent with sound medical practice. These concepts apply to the treatment of all types of pain.

Nonopioid drugs are the most commonly used and are often effective treatment for chronic, noncancer pain. Some effective and commonly used nonopioid drugs include acetaminophen, nonsteroidal anti-inflammatory drugs, and adjunctive agents such as antidepressants and antiepileptic drugs. For headache, specific drugs such as selective serotonin agonists and ergot derivatives are appropriate.

In treating mild to moderate pain, increasing the dose of acetaminophen and aspirin or nonsteroidal antiinflammatory drugs beyond a certain point does not provide increased analgesia. Significant side effects are associated with the use of these drugs, especially when large doses are used over prolonged periods. Acetaminophen can cause hepatic injury or failure, and nonsteroidal anti-inflammatory drugs increase the risk of gastrointestinal bleeding and ulceration and can cause renal damage. Their use is associated with several thousand hospitalizations annually, with elderly people being at disproportionate risk.

The effects of opioid analgesics are mediated by stereospecific receptors (μ, κ, and δ).⁷ Opioid-induced analgesia acts at several sites within the central nervous system and perhaps the periphery as well. Oral, parenteral, transdermal, transmucosal, intrathecal, and epidural administration of opioids can produce analgesia.

Some patients with chronic, noncancer pain respond to nondrug treatment modalities ranging from ice massage to transcutaneous electrical nerve stimulation. Patients, particularly those with substantial disability, which affects their capacity to meet personal, social, or occupational demands, and psychosocial problems, who have not benefited from conventional treatment for pain, are often referred to multidisciplinary pain clinics. These clinics aim to eliminate maladaptive pain behaviors, enable the patient to achieve control of their pain, improve coping through the use of the treatments described above, and to improve psychological functioning, reduce disability, and achieve rehabilitation.

In cases in which less invasive modalities have failed, implantable drug delivery systems (such as intraspinal infusion treatments) are used. In selected patients with severe or unrelenting pain, stimulation of specific central nervous system structures and various neuroablative procedures (such as dorsal rhizotomy, neurolytic nerve block, or intracranial lesioning) have also been used.

Surveys of patients and physicians

The main concern about the use of opioids in chronic, noncancer pain is their safety and efficacy. In a questionnaire completed by patients attending pain centers, 83% of those who were taking opioids reported that the treatment had been at least moderately beneficial. A majority of patients reported no significant adverse effects, and about one-third reported stable dosage requirements and a lack of concern about the possibility of addiction or dependence.

A survey of physicians who were members of the American Pain Society found that many pain specialists believe that long-term opioid treatment is beneficial in selected patients with chronic, noncancer pain; that this treatment is underutilized; and that addiction, tolerance, and physical dependence are generally not significant problems. A national survey also found that a majority of physicians would prescribe long-term opioid treatment for a selected subset of patients with chronic, noncancer pain. Physicians' specialties and geographical location influence their willingness to prescribe opioids, their concern about side effects, and their belief that symptomatic relief alone is sufficient cause to continue the use of opioids.

Several clinical surveys, uncontrolled retrospective studies, and case series on opioid use in patients with this type of pain have been published. Reports encompassing more than 1000 patients have described favorable outcomes in selected samples of patients.⁸^,⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴ Three reports account for about 70% of these patients (table 1).⁹^,¹²^,¹³

Table 1

Summary of large clinical surveys of opioid treatment in patients with chronic pain not caused by cancer

Smaller retrospective surveys have involved diverse patient populations with different diagnoses who were treated with various opioid drugs. Most of these studies are limited by having nonrandomized designs, small patient numbers, and insufficient follow up. The evaluation of outcome often relied on self-reported pain reduction, and different outcomes were selected to indicate success. The results of psychological assessments were generally not reported. Only a few of the studies evaluated changes in functional status, which most pain specialists would agree is important in evaluating the efficacy of treatment in these patients. Documented gains in function were uncommon,¹¹ although patients who had either not benefited from pain clinic programs or who had enrolled in an inpatient treatment program experienced improved function.¹⁰ In a recent study, 12 of 19 patients for whom other treatments had failed responded to dosage titration and fixed interval administration of opioids.¹⁴ Most of these patients had mixed nociceptive and neuropathic sources of pain, and cognition improved in association with analgesic response.

At least 40% to 50% of patients with chronic, noncancer pain evaluated in multidisciplinary treatment programs were already taking opioids.¹⁵ The prescription of opioids for such patients is influenced by the patient's pain behavior (nonverbal communication of pain, distress, and suffering).¹⁶ These programs, and most pain treatment specialists, now endorse an approach that utilizes opioids as an adjunct to a comprehensive treatment strategy using behavioral interventions in combination with other modalities to improve a patient's coping and functional status.¹⁷^,¹⁸

Patients referred to specialized pain clinics are usually more challenging clinically than other patients with chronic pain. Patients at pain clinics tend to have higher levels of psychological distress, greater functional impairment, more work-related injuries, lower levels of education, more frequent surgery for pain, and more frequent reports of constant pain.¹⁹^,²⁰^,²¹^,²² Thus, this population is not representative of the general population of patients with chronic pain.

Several randomized trials have evaluated “opioid responsiveness” in patients with chronic, noncancer pain, particularly neuropathic pain.²³^,²⁴^,²⁵^,²⁶^,²⁷ Clinical experience suggests that opioids are most effective in treating nociceptive pain and less effective in neuropathic pain. In studies using single doses of morphine (5 mg to 20 mg given intravenously), opioids were ineffective in neuropathic or idiopathic pain,²⁴^,²⁸ although comparatively larger doses of alfentanil relieved mechanical allodynia in patients with neuropathic pain.²⁶ Some reports suggest that pain relief in such patients reflects opioid influences on the affective dimension of pain.²⁸^,²⁹ However, other studies in which doses were titrated upward (equivalent to 20 mg to 70 mg morphine) found clear dose-response, analgesic effects in patients with neuropathic pain.²³^,²⁵^,²⁷

Five randomized, controlled trials have investigated the long-term efficacy of opioids in patients with chronic, noncancer pain (table 2).³⁰^,³¹^,³²^,³³^,³⁴ Most involved patients with musculoskeletal pain. Results suggest that titration of dose to either adequate analgesia or intolerable side effects is more effective than the use of fixed doses; effects of opioid treatment on disability, emotional distress, quality of life, and psychological or functional improvement are quite variable; and a subgroup of patients with neuropathic pain does benefit from long-term use of opioids but they are either ineffective or intolerable in many patients with neuropathic pain.

Table 2

Summary of randomized trials of opioids used to treat chronic pain not caused by cancer

Factors that may be useful in determining if a patient is suitable for ongoing opioid treatment include:

Relevant findings on medical and psychosocial history
Patient's response to other therapeutic strategies
The type, intensity, and description of pain
Patient's functional capacity, employment history, and level of social support
Presence of psychopathology and level of emotional distress
Level of coping and the perception of pain and beliefs
Ability to comply with treatment plan
Adverse effects of treatment with opioids
Previous pattern of health care utilization⁵⁹

Patients with well-defined nociceptive pain are the most responsive to opioids. Patients with neuropathic and central pain are less responsive but a small subgroup is responsive. Those patients whose pain syndrome is psychologically maintained are generally not responsive to opioids and are not appropriate candidates for opioid treatment.

Long-term treatment with opioids has not been associated with organ toxicity in cancer patients or patients on methadone maintenance.¹ Most side effects are usually predictable extensions of opioid pharmacology and include respiratory depression, drowsiness, dizziness, nausea, constipation, diaphoresis, decreased sexual function, changes in mood, and pruritus. The occurrence of these side effects may limit the dose that can initially be administered to many patients, interfering with the achievement of adequate pain relief. However, tolerance to most side effects, except constipation, usually occurs, allowing upward titration of the dose until a favorable balance is achieved between analgesia and side effects.

A review of a laboratory and field studies and a large number of studies on the effects of opioids on psychomotor and cognitive functioning in a variety of patients concluded that long-term use of opioids normally should not limit driving or other daily activities.³⁵ This does not extend to patients who are initiating titration or who are consuming other psychoactive agents, and it would also be obviated if overt impairment is observable. Clinicians must be vigilant in assessing patients for cognitive or psychomotor impairment, resorting to formal neuropsychological testing if warranted.³⁶

Analgesic tolerance is not a significant clinical problem for most patients during the treatment of cancer pain.² Most patients with chronic, noncancer pain who are treated with opioids find an effective dose that remains stable for long periods. As with patients with cancer, dose escalation usually reflects progression of a painful lesion rather than drug-seeking, tolerance, or addiction.¹⁰^,¹²

Physical dependence is defined as the emergence of an abstinence syndrome, which occurs in individuals who have been chronically exposed to a particular drug. The abstinence syndrome is triggered by a reduction in or cessation of a dose or by the administration of a drug with antagonist properties. The administration of pure antagonists, mixed agonist-antagonists, or partial agonists can precipitate an abstinence syndrome in someone who is physically dependent on opioids. The physiological changes that underlie physical dependence will not cause problems as long as abrupt abstinence is avoided, and the presence of physical dependence has not precluded the uncomplicated discontinuation of opioids during the management of noncancer pain.

Patients who are physically dependent may experience subtle withdrawal symptoms between doses that manifest as increased pain.²⁰ When these patients increase their opioid dose or frequency of use, they may actually be treating opioid withdrawal.³⁷ Such phenomena may contribute to a pattern of drug use in which pain becomes sustained or maladaptive behaviors manifest themselves.³⁸ This can be minimized with the use of long-acting, controlled-release opioid preparations.

The development of addiction results from an interaction between the inherent reinforcing properties of opioid drugs, such as euphoria or diminished perception of negative feelings or punishment, and predisposing psychological, social, and physiological factors that are uncommon in the heterogeneous population of patients with chronic pain. Tolerance or physical dependence should not be considered diagnostic of addiction in such clinical populations because these are expected consequences of opioid use.³⁸

The prevalence of addiction among patients with chronic, noncancer pain is unknown. There are no systematic longitudinal surveys of heterogeneous populations with this type of pain. The exposure of patients to an opioid does not necessarily elicit behavior consistent with addiction.³⁹ The rates of drug abuse and addiction in patients with chronic, noncancer pain have been estimated at between 3.2% and 18.9%.³⁷^,⁴¹ Higher rates of aberrant drug use have been reported in multidisciplinary pain management programs.¹⁹^,⁴²

Alcoholism or other drug addiction is a contraindication to the use of opioids in patients with chronic non-cancer pain. Treatment of pain in such patients or in those with a history of drug abuse or addiction should include consultation with or referral to an expert who can provide skilled assessment and monitoring.³⁸ Nonetheless, clinicians must always consider the potential for addiction during the treatment of any patient. The experience of pain management programs further encourages caution in the treatment of patients with idiopathic pain, high levels of psychological distress or disability, previous overuse of medical resources, or overuse of prescription or non-prescription drugs.

PSEUDOADDICTION

Some healthcare providers misinterpret the seeking of pain relief in patients with pain as aberrant behavior (that is, patients seeking drugs for nontherapeutic purposes). This iatrogenic syndrome, known as “pseudoaddiction,” manifests as a direct consequence of inadequate pain relief.⁴³ Patients' demands for analgesics increase and they become intensely focused on finding relief when pain is unrelieved. These behavioral changes are driven by the severity of the pain, and the misinterpretation of these behaviors may lead to a breakdown in trust between the patient and physician. The provision of adequate pain relief leads to a resolution of this behavior.

Prescribing by physicians is subject to state laws and regulations, which sometimes are more restrictive than the federal Controlled Substances Act. Prescribing is reviewed by a number of agencies (state justice departments, state medical boards, local law enforcement agencies, and triplicate prescription monitoring programs). State governments have begun to adopt laws that provide immunity from disciplinary action and criminal prosecution for physicians who treat patients with opioids for chronic or “intractable” pain. This is fraught with risks, however, because intractable pain treatment acts have a number of significant limitations such as defining the medical use of opioids as a therapy of last resort; implying that their use be restricted only to those cases in which the cause of the pain cannot be removed; requiring an evaluation of every patient with pain by a specialist in the organ system believed to be the cause of pain; or excluding patients with a history of substance abuse.

The guidelines developed by medical boards also vary considerably in the conditions and qualifications they describe for the use of opioids to treat patients with chronic, noncancer pain.⁴⁴^,⁴⁵ In the past decade, states have adopted or changed laws, regulations, or medical board guidelines to create a practice environment that is conducive to assuring access to appropriate pain relief. To promote consistency in state medical policy, the Federation of State Medical Boards recently adopted model guidelines.⁴⁶ A compilation of the current guidelines is available from the University of Wisconsin's Pain and Policy Studies Group (see methods).

Regulatory policies can perpetuate the undertreatment of pain either by impeding access to controlled substances or by influencing prescribing behavior. The institution of multiple-copy prescriptions caused a large decline in prescribing, some of which is best explained by a change in the behavior of legitimate prescribers.⁴⁷^,⁴⁸

Some concerns about inappropriate scrutiny seem to be legitimate; results of a nationwide survey of members of boards of medical examiners found that many would potentially recommend investigation of a prescriber based solely on the knowledge that an opioid had been administered for longer than 6 months to a patient with noncancer pain.⁴⁹

Several sets of guidelines or consensus statements have been promoted recently to try to create a practice environment that is conducive to effectively managing pain while protecting the public from the illegal diversion of controlled substances.⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸ In a joint consensus statement issued in 1997, the American Academy of Pain Medicine and the American Pain Society noted that opioids are an essential part of pain management and the societal costs of chronic, noncancer pain are substantial. They also acknowledged that chronic pain is often managed inadequately and that accepted principles of practice should be developed. Additionally, the statement said that state legislatures and regulators must recognize the importance of opioids in treating pain and that principles of good medical practice should guide the prescribing of opioids.⁵⁸

Most guidelines on prescribing opioids also acknowledge that good medical practice should guide prescribing (box). Treatments must be individually tailored to patients with chronic pain, and consideration should be given to different treatment modalities. Most guidelines emphasize how best to prescribe long-term opioid treatment and the importance of monitoring to evaluate effectiveness and the patient's functioning. Minimal guidance is provided on which patients should receive opioids or what criteria should be used to select them. Several guidelines suggest that opioid treatment should be contemplated only after adequate trials of other reasonable alternatives. No empirical studies have been conducted to substantiate these guidelines.

CONCLUSIONS

A subgroup of patients with chronic, noncancer pain can benefit from long-term opioid treatment. Although selection criteria have not been adequately validated, these patients usually have one or more identifiable causes for their pain. Generally, they have not responded adequately to other analgesics or techniques of pain management or they may receive additional benefit from the adjunctive use of opioids. These patients experience a reduction in pain and have either functional improvement or are functionally stable on opioids. Patients in this category exhibit a reduction in functioning or an increase in suffering when opioids are tapered off or discontinued.

Recommendations adopted by the AMA on using opioids to treat chronic pain not related to cancer Further controlled trials should be conducted on the use of opioids in patients with chronic, noncancer pain in an effort to:

Identify best practice with regard to the selection of regimens for drug treatment and other modalities
Identify the characteristics of patients that predict opioid responsiveness
Provide support for the development of guidelines on appropriate precautions, contraindications, and the degree of monitoring required in such patients

Further recommendations:

The AMA encourages states to create multidisciplinary task forces or pain commissions to study the barriers to pain management in their state and to make and implement recommendations for policy that will create a practice environment conducive to effective pain management. Guidelines introduced by medical boards are preferable to regulation or statutes.
The AMA and relevant specialty societies should promote educational offerings for physicians to facilitate learning about the principles of the diagnosis and treatment of pain.
The AMA will encourage that appropriate education in pain evaluation and management be provided as an integral part of the core curriculum at all medical schools.

These statements were recommended by the Council on Scientific Affairs at the AMA's annual meeting in 1999

Common elements of guidelines on using opioids to treat chronic pain⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸

Evaluation of the patient
- Obtain a pain history and assess the impact of pain on social, occupational, physical, and psychological function
- Review previous diagnostic studies, other consultations and opinions, and previous surgical and medical interventions
- Review medical, psychiatric, and substance abuse history and assess coexisting diseases or conditions
- Conduct a directed physical examination
Treatment plan and objectives
- Establish a working diagnosis and medical indication for treatment with opioids
- Outline measurable outcome objectives (for example, pain control, improvement in activities of daily living, functional improvement)
- Provide informed consent on the risks and benefits associated with opioids
- Discuss the conditions under which opioids will be prescribed and discontinued
Periodic review
- Assess the safety and efficacy of treatment (for example, subjective pain ratings, functional changes, quality of life, side effects of opioids)
- Assess for compliance and evidence of misuse
- Reassess the nature of the pain complaint to confirm that opioid treatment is still warranted
Consultation
- Referral to a specialist in pain medicine may be warranted depending on the expertise of the practitioner and the complexity of the problem
- Referral to an addiction specialist is often indicated for patients with a history of addiction or substance use disorder
- Referral to a psychiatrist or psychologist may be indicated in cases of significant psychiatric comorbidity
Documentation
- Specific documentation on the following areas should be maintained:
- Evaluation
- Diagnoses (including the reason for prescribing opioids if not obvious from the diagnoses)
- All prescriptions written
- Overall plan to manage pain
- Consultations received
- Written instructions to the patient, the patient's consent, and agreements with the patient

The guidelines that exist to encourage the appropriate use of opioids in patients with chronic, noncancer pain are not treatment algorithms but rather general principles of good medical care. Restrictive regulatory policies on the use of opioids and physicians' fears of regulatory scrutiny continue to play a part in the undertreatment of pain. Until additional controlled scientific data are available, physicians' decisions about opioid use will be based on an evolving clinical consensus influenced by “idiosyncratic, philosophical beliefs created by prior education, populations treated, traditions, myths, and cultural norms interacting with regulatory pressures.”⁶⁰

Notes

Funding: None

Competing interests: None declared

A longer version of this article and the names of the staff of the council can be found on the WJM website, www.ewjm.com.

This report was presented at the annual meeting in 1999 of the American Medical Association. The recommendations were adopted as amended.

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