Editorial III

Opioids for persistent non-cancer pain: recommendations for clinical practice

K. H. Simpson1

1 St James’s University Hospital, Leeds LS9 7TF, UK E-mail: karen.simpson{at}dsl.pipex.com

Pain is the commonest symptom that causes patients to seek health care. Pain is described as persistent when it has been present for about 3 months. Pain may be constant, for example low back pain, osteoarthritis, and post-herpetic neuralgia, or episodic, for example sickle cell crises, osteoporotic fractures, and pancreatitis. Persistent pain affects all age groups, but is commoner in the elderly, when co-existing pathology may limit prescribing and other therapies. The prevalence of persistent pain in the population is difficult to quantify, partly because of problems with case definition; several studies suggest that it occurs in about 10% of people.1 A postal survey of 4600 patients in Scotland who were randomly selected from a general practice database, showed that 16% were moderately to severely disabled by persistent pain.2 In a follow-up study, by the same group, of persistent pain in more than 2000 patients in primary care, 79% of those with pain at initial assessment still had pain 4 yr later.3 This suggests that about 2–6 million people in the UK would describe themselves as having persistent, severe pain not associated with cancer. In England and Wales 1.3–1.75 million people have osteoarthritis, and 0.25–0.5 million have rheumatoid arthritis. The economic burden of musculoskeletal problems is high; it accounts for 1–2.5% of the gross national product of many western countries.4 Back pain is one of the top 10 most costly health conditions.5 In 1998, in the UK, the direct health care cost of back pain was £1632 million, and the cost of informal care and lost production was £10 668 million. The direct costs were distributed as 37% for physiotherapy and allied professionals, 31% hospital, 14% primary care, 7% medication, 6% community care, and 5% radiology.6 Persistent pain is a big problem, and provision of effective treatments has important clinical and economic implications.

Persistent pain is more difficult to treat than acute pain, because of its complex biological, psychological, and social dimensions. Acute pain is usually nociceptive (transmitted by normal pain pathways), but persistent pain is often neuropathic (because of peripheral or central nervous system dysfunction) or it may be mixed. It makes intuitive sense that if pain is managed early, then persistent pain is less likely, but there is little hard evidence for this. However, there are some interesting data that link widespread body pain with excess mortality from cancer.7

Specialist pain management services provide clinically and cost effective management.8 Waiting times are often long, and many patients receive no further active management for their pain within primary care once they have been referred to a pain management service. It is often perceived that all available treatments have been tried. Poor understanding of pain management strategies may be a problem. Specialists should encourage, and be actively involved, in education in primary care. General practitioners need to be informed about a range of pharmacological and non-pharmacological options for managing persistent pain. The use of opioids is topical and important, but any drugs should form only a part of an integrated strategy that aims to improve physical and social function.9 Multimodal therapy is more effective than monotherapy. Pharmacotherapy should be used to facilitate a rehabilitation plan with the aim of improving function; it should involve clear goals, with plans for steady progress towards them. All health care professionals involved in managing persistent pain should address fear avoidance and other behaviours that increase disability.

The World Health Organization analgesic ladder promoted acceptance that adequate, regular doses of opioids such as morphine are needed for moderate or severe cancer pain. The use of strong opioids for non-cancer pain has been less enthusiastic.10 11 but since the 1980s international opinion has suggested that, in a sub-group of such patients, strong opioids can provide analgesia and improve quality of life, without rapidly escalating doses or problem drug use. Although many case series support this, there are few adequate randomized controlled trials. There are several studies that show that opioids relieve persistent musculoskeletal or neuropathic pains, but there are still unanswered questions about their use. Patients with persistent pain can be challenging, as they often have poorly defined pathology, with difficult behavioural and social problems. Many studies are short-term and exclude patients with such problems; therefore the long-term effect of opioids in this group is not fully understood. The use of opioids must be carefully considered and appropriate in this context, and indiscriminate prescribing must not be encouraged.12

Opioids are effective analgesics for some components of nociceptive and neuropathic pain; they are also anti-inflammatory.13 Opioids should not be used as primary anxiolytics or as sedatives. However, an improvement in physical, psychological, and social function and sleep may occur secondary to analgesia. The efficacy of opioids is influenced by many factors, for example neural plasticity, genetic variability in opioid receptors, effects on non-opioid systems, gender and age.14 All opioids are not the same, and individuals may vary in their response to different opioids. Therefore, if one opioid is not effective, an alternative should be tried. Opioid switching was pioneered in the management of cancer pain, but is equally applicable in patients who do not have malignancy.15

Reluctance to prescribe opioids for patients who do not have cancer may be because of concern about side effects that are inevitable when opioids are used. These must be discussed with patients before starting treatment, and managed promptly if they occur. Nausea and vomiting often resolve within days of commencing treatment, but constipation persists and requires active management. Dietary modification and a high fibre diet are often insufficient for opioid-induced constipation, and drug treatment is usually needed. Stimulant and stool softening drugs should be prescribed for all patients taking opioids. Peripherally acting opioid antagonists may be useful for dealing with this distressing side effect.16 Itching may be a persistent problem that necessitates stopping opioids; ondansetron can be helpful for this. Cognitive effects are common when treatment is started or with dose changes; this may be particularly difficult to manage in elderly patients. The cognitive effects of long-term opioids are less clear.17 Many studies suggest that stable opioid treatment does not adversely affect driving skills.18 19 Patients should be reminded about their social responsibilities when taking opioids. Long-term opioid treatment has endocrine and immunological effects;20 the clinical significance of these is not certain. Patients and their partners should be warned of the effects of maternal opioid consumption on neonatal well being if pregnancy is planned. Babies born to women taking opioids have about a 50% chance of showing symptoms of drug withdrawal. The possibility of having to treat neonatal withdrawal syndrome should not, in itself, rule out the use of opioids in pregnancy, if these drugs confer significant benefits to the mother. Adverse effects need to be put into context; opioids are less organ-toxic than many drugs, for example non-steroidal anti-inflammatory agents. Opioids may be a safer option in elderly patients with arthritis.21

Under-treatment with opioids may be because of concerns about patients’ behaviour, tolerance, dependence, and addiction.22 Many of these definitions were developed in the context of drug use in the absence of pain. These terms apply poorly to the prescribed use of opioids as analgesics. Tolerance to opioids used for persistent pain seems to be uncommon; after a period of dose titration that may take several months, the majority of patients stabilize on a long-term dose. Physical dependence is defined by withdrawal when opioid is abruptly stopped, or an antagonist is administered; it is common in patients using a stable opioid dose. It is not important clinically if opioids are tapered during withdrawal. Psychological dependence is compulsion to use the drug; it is rare in patients prescribed a stable dose of opioid for pain management. Addiction means the compulsive use of opioids to the detriment of the user’s physical and/or psychological health and/or social function. The use of opioids prescribed for pain relief probably only rarely results in addiction, although the exact risk is not known. Many studies suggest that the risk is small. It is not possible to use screening tools such as questionnaires to predict the likelihood of addiction for individual patients. The increased medical use of opioids in the 1990s has not resulted in increased health consequences from opioid abuse.23 Pseudoaddiction describes behaviours, for example drug hoarding, attempts to obtain extra supplies, and requests for early prescription or increased dose. These behaviours may be mistaken as addiction, but are an attempt to obtain better pain relief; they cease when pain is managed properly. If problem drug use does occur in the context of treating persistent pain, then it is important to recognize it quickly and act appropriately. Concern that a patient’s behaviour may indicate addiction should trigger immediate referral to and/or consultation with a specialized drug addiction unit. Another reason for reluctance to prescribe opioids is the risk of drug diversion. All health care professionals should be concerned about this, and it is important that every effort is made to prevent it. However, this should not interfere with rational and appropriate opioid prescribing for pain.

More than 20 different oral opioids are available in the UK. Marketing authorization has been given for transdermal fentanyl and transdermal buprenorphine use in patients with persistent non-cancer pain. It is important that opioid prescribing is clinically driven. Many countries have produced recommendations for opioid prescribing in non-cancer pain, and common themes emerge.24 25 Close working relationships and good communication are needed between primary and secondary care services about the management of patients who are prescribed opioids. A doctor should make the initial prescription of strong opioids for persistent non-cancer pain. Other health care professionals may assist with monitoring and maintaining opioid therapy. Psychological co-morbidity, social chaos or a history of alcohol/problem drug use do not absolutely preclude the use of opioids. Advice from, or referral to, a specialized service with experience of managing these patients (e.g. multidisciplinary pain management service or specialized addiction service) is recommended in these circumstances. Health care professionals who prescribe or maintain opioid treatment for persistent non-cancer pain should develop an individualized treatment plan in each case. Patients should be aware of the limitations and side effects of opioids, and of their responsibilities within the treatment plan. The primary outcome of treatment should be pain relief. Demonstrable improvements in physical, psychological, and social function are important secondary aims. Modified release or transdermal opioids are preferable; immediate release formulations should be avoided. Injectable opioids are rarely appropriate in the management of persistent non-cancer pain. Patients who are prescribed opioids for persistent non-cancer pain should be assessed regularly at intervals determined by clinical need. The assessment should include documented evaluation of: pain relief; physical, psychological and social function; sleep; side-effects; and signs of problem drug use.

The Pain Society in the UK is developing recommendations for the use of opioids in persistent non-cancer pain (available at www.painsociety.org). It is difficult to strike a balance between a document that is so general as to be almost useless, or so proscriptive that it becomes limiting. However, it is hoped that these recommendations will aid appropriate prescribing and will form the basis for development of more detailed local policies.

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