Chronic opioid therapy for non-cancer pain

B.-J. Collett

Pain Management Service, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester LE1 5WW, UK


    Abstract
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 Abstract
 Introduction
 Epidemiology of chronic pain
 Epidemiology of opioid use...
 Are opioids effective for...
 What are the arguments...
 Guidelines
 References
 
Br J Anaesth 2001; 87: 133–143

Keywords: analgesics opioid; pain, chronic non-cancer


    Introduction
 Top
 Abstract
 Introduction
 Epidemiology of chronic pain
 Epidemiology of opioid use...
 Are opioids effective for...
 What are the arguments...
 Guidelines
 References
 
Opioids are the most potent and effective analgesics available and have become accepted as appropriate treatment for acute and cancer pain. However, there is concern regarding their usage in chronic non-cancer pain because of fears that they are ineffective in the long-term, that their use will lead to a deterioration in the patient’s condition and that the medical prescription of opioids will lead to an increase in their non-medical use within society. In certain countries, physicians may also fear triggering scrutiny and sanctions by regulatory agencies when prescribing long-term opioids for chronic pain of non-malignant origin.18 48 92 However, relief of pain is a humanitarian issue and it has been said that ‘to leave a person in avoidable pain and suffering should be regarded as a serious breach of fundamental human rights’.87


    Epidemiology of chronic pain
 Top
 Abstract
 Introduction
 Epidemiology of chronic pain
 Epidemiology of opioid use...
 Are opioids effective for...
 What are the arguments...
 Guidelines
 References
 
Chronic pain is a common complaint within the community and a common cause of distress and disability. A telephone survey of 1037 randomly selected households in the UK concluded that, out of a total household population of 2942 individuals, 208 adults (7%) experienced intermittent or persistent pain from non-fatal causes that lasted for at least 3 months.8 Fifty-five per cent stated they were unable to lead a normal life because of the pain. A recent Scottish study indicated a higher incidence of chronic pain or discomfort (46.5%) in the community.27 Half of those in pain had severe or disabling pain. Back pain and arthritis were the most common causes of pain, accounting for one-third of all complaints. Chronic pain was associated with older age, retirement, or inability to work. Other studies amply demonstrate that recurrent and chronic pain is a major public health problem.24 Poor management of such pain has important consequences for individual patients, their families, and society.


    Epidemiology of opioid use for chronic non-cancer pain
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 Abstract
 Introduction
 Epidemiology of chronic pain
 Epidemiology of opioid use...
 Are opioids effective for...
 What are the arguments...
 Guidelines
 References
 
Sorenson and colleagues investigated the use of opioids outside hospitals in Denmark.88 Their sample of 480 000 represented almost 10% of the Danish population. During the 1-month study period, strong opioids were prescribed to 633 patients (0.2% population). In 110 patients (17%), the indication was pain as a result of malignancy. In 387 patients (58%), the indication was for chronic non-malignant painful conditions, which included back pain (25%), headache (10%), arthritis (9%), pancreatitis (6%), angina pectoris (5%), and phantom pain (5%). In 69 patients, strong opioid was prescribed for recurrent acute pain—the most common indication being migraine. They concluded that only a small number of patients with chronic pain within the community (estimated prevalence 30%) were being treated with strong opioids.

In Australia, over a 10-yr period from 1986 to 1996, the amount of oral morphine consumed for pain control increased fivefold from 117 to 578 kg. Use in non-malignant pain accounted for much of this increase. In a sample of patients being treated with opioids for non-cancer pain, one-third continued using opioids for 5 yr or more and this usage was associated with dose escalation. Many patients had poorly defined medical problems and social and emotional problems were common.6

There have been several surveys of opioid prescribing habits for non-malignant pain amongst pain management specialists. In the UK, Coniam surveyed physician members of the Intractable Pain Society regarding opioid prescription for non-malignant pain. Sixty-two per cent of respondents indicated that they did prescribe opioids for non-malignant pain, the predominant reason being failure of other treatments. However, 81% reported some problems with patients on long-term opioid therapy, the most frequent being intolerance to side effects, which was reported by 63.8% of respondents.23 The Clinical Standards Advisory Group (CSAG) study ‘Services for patients with pain’ reported that 75% of pain management clinics in the UK currently provide supervised opioid therapy for non-cancer pain.19

Turk and Brody surveyed members of the American Pain Society and reported that 83% maintained some patients on opioid therapy. Generally, the respondents believed that opioids were under-utilized and that addiction was over-emphasized.92

However, pain specialists do not treat most patients with pain. A random sample of 6962 American doctors from seven specialities (excluding pain management) suggested that the respondents (1912 doctors) relatively infrequently prescribed opioids for patients with chronic non-cancer pain.91 Rheumatologists treated more chronic pain patients and prescribed long-term opioids more frequently than any other speciality in the survey.

The triggers for a doctor to prescribe opioids for a particular patient requires further investigation. Data from patients attending a pain treatment centre suggest that prescribing practice did not appear to be influenced either by the extent of pathology or by pain severity. Patients who displayed high levels of observable pain behaviours and reported high levels of functional impairment were significantly more likely to be prescribed opioids.93

There is a clinical impression in the UK that opioids are only given as a last resort. Yet in 1995, 4.13 million prescriptions for opioids were written in England alone.


    Are opioids effective for chronic non-cancer pain?
 Top
 Abstract
 Introduction
 Epidemiology of chronic pain
 Epidemiology of opioid use...
 Are opioids effective for...
 What are the arguments...
 Guidelines
 References
 
Published patient surveys and case-reports support the efficacy and safety of long-term opioid analgesics in carefully selected patients with chronic non-malignant nociceptive and neuropathic pain.7 35 68 84 89 90 96 102 Patients themselves report positive preference for opioid medication.2 45 98

A criteria-based methodological assessment of eight randomized controlled trials (RCT) of efficacy of opioids in non-malignant pain has recently been reported.37 Methodo logical quality of the trials was assessed and agreed by three independent reviewers against 14 criteria and the types of pain (nociceptive, neuropathic, or idiopathic) studied in each trial were identified (Table 1). Some of these trials are infusion or injection studies and some are longer-term studies of oral or sublingual opioids.


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Table 1 Overall outcome of RCTs on opioid therapy for different chronic non-cancer pain syndromes.37 +=positive effect; –=no effect; #=significant adverse effects (adapted from Graven et al.37)
 
The authors concluded from these trials that nociceptive pain responds well to opioid therapy3 49 and that neuropathic pain responds reasonably well, although slightly less favourably.3 26 52 76 Patients with so-called idiopathic pain tend not to respond to opioids.3 52 60 Patients tended to report favourable effects from opioids in the two studies that did not specify the diagnoses.2 55

Jadad has recently conducted a systematic review of randomized controlled clinical trials of opioids in neuropathic pain.43 He identified nine trials that evaluated 104 patients in total. The trials had small sample sizes, heterogeneous patient populations, and designs. Some of the trials used fixed dose administration and, in some, the dose was titrated. However, he concluded that the best available evidence appears to support the contention that neuropathic pain can respond to opioids.

Table 2 shows the reported efficacy of opiates on different pain syndromes from prospective uncontrolled trials.37 These studies reveal similar results to the RCT and, as expected, the positive effects from these trials are larger and more frequent than in the prospective controlled series.


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Table 2 Overall efficacy of opiates on different pain syndromes (prospective uncontrolled studies).37 +=positive effect; –=no effect; +/–=mixed effects
 
A recent review of the limited literature regarding opioid efficacy in ischaemic pain has concluded that further research is needed before recommendations can be made.66


    What are the arguments against using opioids long-term for chronic non-cancer pain?
 Top
 Abstract
 Introduction
 Epidemiology of chronic pain
 Epidemiology of opioid use...
 Are opioids effective for...
 What are the arguments...
 Guidelines
 References
 
Brena has argued that the needs of the chronic pain patient include not only reduction in subjective discomfort but also increase in general level of functioning, improvement in lifestyle, decrease in environmental stress and return to work. Whilst the first need may be met through opioid analgesia, he questions how well the other needs will be met.9 Completion of a multidisciplinary pain rehabilitation programme can result in a significant reduction in use and misuse of medications. This reduction can be associated with a decrease in pain intensity, an improved sense of well-being and an increase in physical activity, return to work and ability to manage pain and related problems.9 32

Functional outcomes
Conflicting results have been obtained from studies investigating the effects of chronic opioid therapy on physical and psychological functioning.2 35 39 47 60 98 A reduction in pain intensity was accompanied by an improvement in the overall Pain Disability index (PDI) score and in most of the PDI sub-scales in one study comparing controlled-release codeine with placebo.2 In a study of elderly patients with post-herpetic neuralgia, oxycodone reduced pain, allodynia, and disability scores compared with placebo.98

In contrast, although Moulin reported analgesic benefit from morphine, patients did not show any improvement in physical or psychological functioning.60 Jamieson reported alleviation of pain and mood improvement, but no increase in activity levels in patients with chronic back pain. In this study, patients showed a preference for the short-acting opioid (oxycodone) as compared with the sustained-release morphine. They rated oxycodone as more helpful and reported being more confident in the knowledge that they had access to short-acting opioids should the pain flare up. Patients who varied their opioid dose from week to week reported less pain and better mood than those who did not. This runs counter to previous argument that taking opioid on a pain-contingent basis increases the likelihood of reinforcement of pain behaviour and dosage increase.47

Adverse outcomes
Organ toxicity
From clinical experience with the cancer pain population, the chronic non-cancer population and in the ‘methadone-maintained’ population, it would appear that long-term opioid therapy is not associated with major organ toxicity.51 89

Effects on the immune system
There is an increasing body of evidence, obtained both from in vitro and in vivo studies in animals and humans, showing that exogenous opioids are able to suppress a variety of immunological responses.15 28 61 75 In humans, most data are based on the evaluation of immune function in i.v. heroin users and methadone-maintained patients (MMPs).62 74 However, effects have also been shown in human volunteers99 and post-operative patients.77 A recent study investigated immune responses in 10 patients with pain (seven non-malignant and three because of cancer) before and after treatment with sustained-release morphine and compared them with eight healthy control subjects not taking morphine. The cellular immune responses did not initially differ between patients and controls and did not show any significant changes during treatment. Immunoglobulin (Ig) production was reduced in the chronic pain patients before morphine was commenced and further reduced by morphine therapy. The clinical impact on the immune system as a whole of this suppression of humoral response remains to be elucidated.63 It has been suggested that chronic opioid administration can induce a state of immune tolerance with normal resistance to viral infections.12 75

It is apparent that this is an area in which a better understanding of these interactions has important clinical implications.

Pain facilitation
Hyperalgesia has been reported after systemic administration of high-dose morphine in cancer patients. There is some evidence that long-term use of opioids can induce a similar state of hyperexcitability of the central nervous system.5 Current opioid use has been associated with decreased pain tolerance.21

Clinically, it has been recognized that some patients have an improvement in their pain after opioid reduction or withdrawal. The potential clinical ramifications of the effects of opioids on pain modulatory systems are important if they are to be increasingly prescribed to patients with a normal life expectancy.

Persistent side effects
Opioids produce clinically significant side effects, such as respiratory depression, sedation, cognitive impairment, nausea, itching, and constipation. In some patients, and especially in the elderly, adverse drug reactions can prevent the use of opioids.49 60 Whilst tolerance develops to many of these adverse effects, some remain and may be regarded as important in long-term use.

In a methadone maintenance programme, increased sweating was the most common side effect reported (48%). Constipation was also a common problem and all patients required daily laxatives in the first year. However, after 3 yr or more of methadone treatment, constipation was a persistent problem in only 17%. Insomnia and decreased libido and sexual functioning were also reported.51

Cognitive impairment
Cognitive impairment is a side effect that is potentially important with regard to long-term administration for non-malignant pain as this may affect driving, working ability, and may compromise engagement in a rehabilitation programme.

Early studies and case-reports have emphasized the negative effects of opioids, tranquillizers and sedatives/hypnotics in chronic pain patients, particularly with respect to cognitive functioning and personality.54 56 Long-term use of tranquillizers appears to be associated with a greater risk of cognitive deficits compared with long-term opioid use.40

A recent comprehensive review has evaluated the available data on the effect of different opioids on a variety of psychomotor and cognitive tests in different populations (mainly volunteers and illicit opioid users).101 Impairment by opioids tends to occur more often in healthy volunteers (who have little or no prior exposure to the drugs) than in those who have a history of opioid use. In general, for healthy volunteers, cognitive performance seems to be less impaired than psychomotor performance, for example, behaviour tends to ‘slow down’ rather than become more erratic.

For opioid-dependent users, laboratory studies show little if any cognitive impairment on multiple measures.101 A recent study from Australia has shown cognitive deficits in MMP when compared with non-heroin-using controls. However, there was no correlation between the extent of impairment and methadone dosage and the researchers concluded that hypoxic brain damage from previous overdose, traumatic brain damage and alcohol-related brain damage amongst the MMPs were the three most important contributing factors.25

Pain itself has been shown to impair cognitive function and, therefore, studies performed to evaluate cognitive effects of opioids in pain-free controls cannot necessarily be extrapolated to patients in pain.53 Pain may have an arousal effect and counter-act the sedative effects of opioids.

Continuous reaction time (CRT) is reduced in cancer patients on oral opioids compared with healthy controls.85 Cancer patients with reduced performance status, in pain and on oral opioids have impaired neuropsychological functioning when compared with cancer patients with no pain and no disability. However, the use of long-term opioids per se does not affect any of the neuropsychological tests and pain itself appears to interfere with working memory more than oral opioid medication.86 Bruera and colleagues demonstrated evidence of significant cognitive impairment in a group of patients who had recently had their opioid dose increased compared with those patients on a stable dose. Patient self-report indicated that patients themselves might be less aware of cognitive impairment than other opioid-induced side effects.11

In patients with non-cancer pain, no deterioration in cognitive function has been detected during long-acting opioid treatment and indeed an improvement on a measure of sustained attention and psychomotor speed was observed as pain intensity decreased during opioid usage.39

Driving
Vainio and colleagues specifically addressed the question of opioid-induced cognitive impairment in cancer patients in relation to driving. Psychomotor and neurological tests designed for professional drivers were conducted in two groups of cancer patients; one group was pain free and the other took regular oral morphine. There were no significant differences in most of the tests between the groups, although patients taking morphine did tend to show slower reactions, make more errors, and perform motor tasks more slowly. However, no differences existed in important functions related to driving, such as concentration and vigilance and mean performance levels in both groups were comparable with that of healthy volunteers.97 They concluded that long-term stable opioid therapy does not affect psychomotor performance such that driving would be hazardous.

Most epidemiological studies suggest no increased risk of accidents (including road traffic accidents) and injuries amongst those who use opioids.101 The relative risk of involvement in a road traffic accident for current users of any psychoactive drug has been reported as being 1.5 (95% confidence interval: 1.2–1.9). Regression analysis revealed that the type of psychoactive drug used was a factor: relative risk was not greater than 1 with oral opioid analgesics but was higher than 1 with benzodiazepines and antidepressants (e.g. amitriptyline).

Analysis of bodily fluids taken from fatally injured drivers in California and in Norway revealed that alcohol, cannabinoids, cocaine, and benzodiazepines were most frequently found. Samples rarely contained opioids.

Further studies on simulated and active driving are needed to gain a more comprehensive picture of the effects of opioids and of multiple medications on driving ability in patients with chronic non-cancer pain.

Clearly, patients should be warned to avoid activities like driving if they experience mental clouding and also about the possible additive effects of other centrally-acting drugs, such as alcohol or tricyclics.

Decision-making
Further studies are need to address whether chronic opioid therapy might impair decision-making in the work-place, although data so far suggest that this should not be so.

Elderly
There are important concerns about sedation and cognitive impairment in the elderly, especially in relation to falls. A review of 4500 patients with hip fracture compared with 24 041 hospitalized controls revealed an increased relative risk of fracture of 1.6 among those who were taking codeine or propoxyphene, especially if medication had been recently commenced.83 Concurrent users of these opioids and psychotrophic drugs further increased their risk of hip fracture to 2.6 times that of non-users of either drug class.

Chronic pain is common in older people and often under-treated. Paracetamol may not provide adequate pain control. Chronic use of non-steroidal anti-inflammatory drugs is associated with a high frequency of adverse effects. Older people appear to be more sensitive to the analgesic effects of opioids as well as to the side effects. Low initial dosing of analgesics is required for all elderly patients with careful titration and monitoring and due recognition of a vulnerability to all opioid side effects.1

Tolerance
Tolerance refers to a phenomenon in which exposure to a drug results in the diminution of an effect or the need for a higher dose to maintain an effect.44

Tolerance to the antinociceptive effects of opioids can be demonstrated in animal models and tolerance to the analgesic effects of opioids after acute and chronic dosing has been clearly shown in man.17 42 57 Tolerance to the adverse effects of opioids also occurs and has positive benefit. There is a suggestion from animal research that ongoing nociception may modulate the development of tolerance to analgesic drugs. Many cancer patients with severe pain often have long periods of stable opioid dosage unless disease progression occurs.10 20 34 81 95 Clinical surveys of long-term opioid use in patients with non-cancer pain, when an increasing nociceptive focus is unlikely, have not shown escalating drug dosage to be an inevitable clinical problem, although some dose increase is often observed over time.31 35 64 67 90 96 100 102

Management of tolerance
Clinicians must evolve strategies for managing increasing analgesic dose and possible tolerance in the patient with non-cancer pain. Principles that have been effective in the management of tolerance in the cancer patient would seem appropriate: (1) the ‘differential diagnosis’ for declining analgesic effectiveness should be considered and treated,70 (2) the dose of opioid can be increased, (3) an alternative opioid can be substituted at a reduced dose, and (4) alternative pain management strategies can be introduced with dose stabilization or reduction.

Physical dependence
This has been defined as ‘the potential for an abstinence syndrome, or withdrawal, following abrupt dose reduction, discontinuation of the drug or administration of an antagonist drug’.44 Symptoms and signs of withdrawal are described in Table 3.


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Table 3 Symptoms and signs of opioid withdrawal
 
Physical dependence should be assumed to exist if opioids have been given repeatedly for a few days. However, 55% of arthritis patients prescribed long-term opioids reported that they did not take their medication on a daily basis because of fear of dependence and addiction. Withdrawal symptoms were not spontaneously reported.100 Although, with regular opioid medications, overt withdrawal is unlikely, it has been postulated that subtle episodic withdrawal symptoms may increase baseline pain and associated problems such as mood and sleep disturbance. This might explain the improvement reported by some patients when short-acting opioids are reduced and eliminated or replaced with long-acting medications.79

In cancer patients, withdrawal symptoms do not appear to be problematic provided opioids are withdrawn slowly81 and, if they do occur, they can be controlled by resumption of a small dose of opioid.95 Withdrawal symptoms do not appear to be a barrier to opioid reduction in non-cancer patients within the setting of a pain management programme.13 72

Addiction
Studies in the 1920s and 1950s were influential in supporting the notion that chronic opioid therapy leads to addiction. Between 9 and 27% of addicts reported that their first exposure to opioids was as a result of a therapeutic prescription for pain.50 73 However, these studies have methodological flaws and more recent reports have suggested that the risk of iatrogenic opioid addiction is very low.65 714


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Table 4 American Society of Addiction Medicine definitions related to the use of opioids in pain treatment22
 
Addiction is a complex phenomenon, with several components: genetic, environmental, psychological and the inherent properties of the drug itself. Current evidence suggests that the development of addiction is a result of, in part, to neurochemical stimulation of reward centres in the limbic system and related areas of the brain. Most addiction specialists agree that the alcoholic, or other drug-addicted individuals should be viewed as being at risk for addiction to substances other than their drug of choice.78 The course of addictive disease may be variable from individual to individual and an addictive pattern of drug use may occur at any time because of a combination of factors. With treatment and/or abstinence, the individual may recover. Nevertheless, the disease of addiction, once evolved, is conceptionalized by most addicitonists as incurable.

Prevalence
Current estimates from North America indicate that between 3 and 19% of chronic pain patients suffer an addictive disorder, which parallels the lifetime prevalence rates of addictive disease in the general population (3–16%).33 A recent Swedish study of 414 patients referred to a chronic pain centre and indicated a higher prevalence (23.4%), with 9.4% additionally meeting diagnostic criteria for substance use disorder in remission. Current dependency was most common for analgesics (12.6%), alcohol (9.7%), and sedatives (7.0%).41

Savage has identified reasons why the incidence of addiction may be higher in patients with chronic pain compared with the non-pain population.78 First, traumatic injury is often the initiating factors in the development of chronic pain and there is a relatively high incidence of alcoholism amongst individuals who sustain trauma. One study found that 49% of individuals with spinal cord injury screened positive for alcoholism. Alcohol is thought to be a factor in over 50% of road traffic accidents. Second, some studies have suggested an association between childhood sexual or physical abuse and the development of chronic pain. Physical and sexual abuse occurs more commonly in families in which one or more parent is alcoholic. If the children of alcoholics are over-represented in pain clinics for whatever reason, then it should follow that addictive disease will be more common, as the children of alcoholics are more likely to develop alcoholism and other addictive disease. Third, there is accumulating evidence regarding interrelationships between the neurophysiological pathways that mediate pain and those that mediate addiction. Fourth, chemical dependency itself may sustain the pain. Lastly, addicted individuals often cannot fulfil their usual work and domestic roles, suffer financial losses and relationship problems and may develop secondary physical complaints. This may feed into a chronic pain-distress/impairment cycle.

Identification
Alcoholism and other addictions are underdiagnosed in a medical setting. Common reasons for underdiagnosis include:

1. Lack of skill in recognition on the part of the doctor.

2. Uneasiness about discussing drugs and alcohol.

3. Unfamiliarity about resources available for treatment.

4. Belief that the condition is untreatable.

5. Belief that the condition is moral rather than medical.

6. Belief that the addiction is secondary to the pain with the expectation that it will resolve when the pain is successfully treated.

7. Belief that it is a totally independent problem and, therefore, not of concern of the doctor in the pain clinic.

Experience suggests that pain in patients with addictive disease does not improve unless their addiction is also treated.32

The clinician should make some conscious effort to identify the alcoholic or addict in the pain management clinic. History, physical examination, and laboratory studies (including elevated GGT and MCV) may be helpful.

Several short screening tests for alcoholism have been developed such as the CAGE questionnaire. (C=Have you ever felt you ought to Cut down on your drinking? A=Have people ever Annoyed you by criticizing your drinking? G=have you ever felt Guilty about your drinking? E=Have you ever had an ‘Eye-opener’ first thing in the morning to steady your nerves or get rid of a hangover?). Equally important is identifying the individual who is in recovery. All individuals in recovery are at lifetime risk of relapse. Many addiction specialists recommend avoidance of all potentially intoxicating or dependency producing medications. Involvement of a specialist in addiction medicine may be appropriate if features of addiction are present on initial examination.32 82

The American Society of Addiction Medicine has recognized the limitations of the DSM-IV criteria for diagnosing addiction in chronic pain patients treated with opioids. Separate recommendations for defining addiction in this group have been developed and are shown in Table 4.22

Addiction in the context of pain treatment with opioids is characterized by a persistent pattern of dysfunctional opioid use that may involve any or all of the following:

adverse consequences associated with the use of opioids;

loss of control over the use of opioids;

pre-occupation with obtaining opioids despite the presence of adequate analgesia.

‘Prescription opiate abuse’
‘Prescription opiate abuse’ has been used to define misuse of prescribed opiate medications by patients in the clinical setting who are being treated by a physician for a recognized pain condition.16 A set of behaviours that suggested, or were consistent with, opiate abuse was formulated and patients attending the pain clinic were assessed according to these criteria.

A patient qualified as a ‘prescription opiate abuser’ if they met three or more of the following criteria.

(a) Patient displays an overwhelming focus on opiate issues during pain clinic visits that occupy a significant proportion of the visit and impede progress with other issues regarding the patient’s pain. This behaviour must persist beyond the third clinic treatment session.

(b) The patient has a pattern of early prescriptions (three or more) or escalating drug use in the absence of acute change in his/her medical condition.

(c) The patient generates multiple telephone calls or unscheduled visits to request more opiates, early prescriptions or problems associated with opiate prescription. A patient may qualify with fewer visits if he/she creates a disturbance with the office staff.

(d) There is a pattern of prescription problems for a variety of reasons that may include lost, spilled or stolen medications.

(e) The patient has supplemental sources of opiates obtained from multiple providers, emergency departments or illegal sources.

Seventy-six out of 403 pain clinic patients, who were using opioids for longer than 6 months, were rated independently against the above criteria by two physicians. Twenty-one (27.6%) met three or more of the five possible criteria for prescription opiate abuse.16 ‘Drug-seeking’ behaviour, particularly surrounding prescriptions, would seem to be ‘relatively more predictive’ of addiction.16 22 69 Family members and the patients themselves may also have insight into whether the patient is addicted.22

Previous history of addictive disease
There are conflicting data concerning a previous history of drug abuse or alcoholism. Some studies have shown no differences between the abusers and non-abusers for a history of previous drug or alcohol abuse.16 100 In other studies, a previous history of addictive disease has been positively associated with prescription drug misuse.22 As there is no proven method for identifying patients at risk of addiction, this must be viewed as a potential risk.

Diversion and non-medical use
All opioids have a street value and may be traded or sold. This applies to weak opioids such as dihydrocodeine as well as to strong opioids, and to long-acting as well as short-acting formulations. Currently, in Leicester, one MST 30 mg tablet costs £3.00 ‘on the street’ (personal communication).

The 1999 National Household Survey on Drug Abuse (NHSDA) released by the Substance Abuse and Mental Health Services Administration indicated there were 2.6 million Americans reporting analgesic use for non-medical reasons. An estimated 1.6 million people used prescription analgesics non-medically for the first time in 1998, representing a significant increase since 1990 when there were 564 000 initiates (Fig. 1).



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Fig 1 Annual numbers of new users of pain relievers non-medically 1990–1998. Source: Substance Abuse and Mental Health Services Administration, Office of Applied Studies, National Household Survey on Drug Abuse, 1999.

 
Physicians need to be aware that drugs they prescribe may be diverted. They have a responsibility to perform a thorough assessment of risk factors and to develop practices to ensure that their patients are taking medication as prescribed. A single prescriber is advisable. Close liaison with the General Practitioner is essential as they may be better informed of aberrant behaviour than the hospital specialist. However, physicians should not withhold opioids from an individual patient requiring strong analgesics because of general concerns regarding diversion.


    Guidelines
 Top
 Abstract
 Introduction
 Epidemiology of chronic pain
 Epidemiology of opioid use...
 Are opioids effective for...
 What are the arguments...
 Guidelines
 References
 
It would appear that there is a consensus view that a subset of patients with chronic non-malignant pain may have less pain and function better if treated with opioids.29 46 69 80 Critical questions which must be addressed to ensure the maximum benefit for the prescription of opioids for chronic non-malignant pain are as follows.

Who are appropriate patients?

Who are appropriate prescribing doctors?

How should opioids be initially prescribed?

Which opioids?

Informed consent.

What are appropriate outcome measures?

Review.

How and when should the opioids be withdrawn?

Guidelines have been proposed to assist practitioners to identify those patients who are suitable for chronic opioid therapy and to suggest how they may best be managed.14 38 59 69 80 94 102 In May 1998, the Federation of State Medical Boards of the United States, Inc. released a policy document entitled ‘Model guidelines for the use of controlled substances for the treatment of pain’ and this is available on the internet at: (http://www.medsch.wisc.edu/painpolicy/domestic/model.htm).

There are common elements to many of these guidelines, which may be summarized as follows.

Evaluation of the patient
The doctor should perform a thorough history and examination of the patient. This should include a pain diagnosis, including an estimate of nociceptive, neuropathic and psychosocial contributions, current and past treatments, functional impairment, and history of substance abuse.

There is general agreement that opioids for non-cancer pain should only be prescribed after all other reasonable attempts at analgesia have failed and should be a part of a comprehensive treatment approach. Patients with a past history of substance abuse should not necessarily be denied a trial of opioid therapy, but will require more careful prescribing and follow-up. It has been suggested that either an i.v. or spinal opioid challenge should be administered to assess opioid-responsiveness. Whilst this may aid decision-making in difficult cases, for most patients, low-dose oral opioids with gradual dose titration will suffice.

Treatment plan
The primary purpose of long-term opioid therapy should be improved quality of life for the patient. The patient and clinician need to negotiate an individualized treatment plan to find the optimum balance of pain relief, functional improvement, and side effects. Emphasis should be placed on capitalizing on improved analgesia by an increase in physical and psychosocial functioning.

An initial trial of therapy with goals and an end-point agreed between the physician and patient should precede any decision with regard to long-term treatment. Failure to achieve partial analgesia with incremental dose increases may indicate a non-responsive pain syndrome. A single clinician should take primary responsibility for drug prescribing, at least in the early stages of treatment.

Most of the guidelines suggest the use of a long-acting opioid preparation on a time-contingent basis. The rationale for this is that more stable concentrations of drug in the blood can be attained, thereby allowing better tolerance to side effects and a reduction in the possible reinforcement of pain behaviour that can occur when analgesics are taken on a pain-contingent basis. However, chronic pain patients are a heterogeneous group and some patients with low back pain have shown a preference for short-acting medication, with no evidence of inevitable dose escalation.47 Injectable opioids should not be used to treat chronic non-cancer pain.6 30 In particular, i.m. pethidine should be avoided. It has a short half-life and the potential for excitatory central nervous system toxicity from accumulated norpethidine concentrations after repeated doses.

Informed consent
Physicians should discuss the risks and benefits of opioid therapy. Points to be covered should include likelihood of physical dependence, potential for cognitive impairment, particularly after dose increase or if taken with other sedative drugs, and recognition of the risk of addictive behaviour. Some guidelines suggest written contracts for patients at high risk of non-compliance.

Periodic review
Ongoing assessment is an essential part of the management of the patient with opioid therapy and should take place at reasonable intervals based on the individual circumstances of the patient.

In evaluating the efficacy of opioid therapy, it is recommended that the following points be covered:

patient’s self-report of pain;

level of physical and psychological functioning;

side effects of opioid therapy;

any suspicious drug-seeking or aberrant behaviours;.

any changes in drug dosage to be recorded and the reasons for them;

correct procedures to be followed for writing prescriptions.

Dose escalation needs to be comprehensively assessed and managed according to cause. The adverse effects of opioid therapy may sometimes lead to a persistent decrease in function. In some cases, a gradual reduction in dose— possibly leading to discontinuation of therapy—may be indicated. Information from family members and friends may be helpful.

Consultation
Referral to other specialists, such as a Consultant Psychiatrist with expertise in addiction medicine, should be considered for those patients who develop symptoms of drug misuse.

Documentation
Documentation is essential to demonstrate the evaluation process, the rationale for long-term opioids in the context of the overall management plan, informed consent and periodic review of the status of the patient.

No empirical studies have been conducted to substantiate these guidelines. If guidelines are to be widely accepted, they must be applicable to the range of patients that present with severe intractable pain. Patients that might be considered for opioid therapy may have a wide range of diagnoses and may be treated in a variety of settings, for example, primary care, rheumatology, neurology, and pain management clinics. Patients in pain management clinics and especially pain management programmes may have a high rate of psychopathology, abnormal pain behaviours, abnormal family, social and work situations and disability factors that may make treatment with opioids more difficult.

The currently available guidelines all suffer from a local cultural and legal bias depending on their country of origin. A case has been made for specific guidelines for use in the UK to be researched and formulated.

Clearly, the treatment goals in chronic non-malignant pain are a reduction of symptoms and suffering as well as functional improvement, decreased dependence on the health care system and return to work and social functioning. Analgesics are only part of this treatment. There may be a population of patients who clearly benefit from opioids and we need to identify who they are and how they can best be managed.


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 Abstract
 Introduction
 Epidemiology of chronic pain
 Epidemiology of opioid use...
 Are opioids effective for...
 What are the arguments...
 Guidelines
 References
 
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