H J McQuay DM, Clinical Reader in Pain Relief
Pain Research; Nuffield Department of Anaesthetics, University of Oxford, Oxford UK
Abstract
Many of the important questions for those who prescribe opioids in chronic pain, and important for those who take the drugs, still have to be answered with inadequate evidence, because we lack randomised trials on these topics
Two of the principal reasons for 'failure' of opioids to relieve pain, incident pain and neuropathic pain, are discussed. Some specific adverse effect problems are addressed, and the paper concludes with a section on the vexed issue of opioid prescription in non-cancer pain.
If we take in our hands any volume ... let us ask, "Does it contain any abstract reasoning concerning quantity or number?" No. "Does it contain any experimental reasoning concerning matter of fact and existence?" No. Commit it then to the flames, for it can contain nothing but sophistry and illusion."
David Hume (1711-76)
Much of our prescribing of opioids is based on opinion rather than on evidence. In part this is because opioid use in chronic non-cancer pain is an orphan area, in part because trial design and conduct is not easy in this patient group, and in part it is historic - many opioids are old drugs, and the registration trials required for new drugs have therefore not been done. It is remarkable how little new evidence on oral and intramuscular opioid use has emerged since earlier reviews [1, 2, 3]. An added complication is that there is a plethora of routes by which these drugs can be given. The fact "that it can be done" very often pre-empts the more important question "should it be done?". Enthusiasts for the new route carry it into practice without adequate comparison of risk and benefit with 'established' routes. Again these arguments have been well rehearsed [4]. Much of the 'new' evidence for spinal or transdermal opioids does not answer the real clinical questions.
Clinical aspects
Effectiveness
Success
Just how effective are opioids in managing chronic pain, cancer or non-cancer? The assumption from audits of applying WHO guidelines (Figure 1) in cancer pain is that two-thirds of patients achieve good or moderate pain relief.
The adequacy of these audits has been challenged on process grounds [5]. In practical terms we have refrained from detailed questioning of the adequacy of our methods because of a wider public health political goal, which is to achieve better coverage of the world population with implemented WHO guidelines (and sufficient drug supplies).
In attempting to update the WHO guidelines questions emerge such as whether a second stage is necessary and whether a fourth stage should be added [6], and yet again there is the problem that little research evidence answers these clinically relevant questions. Both existing guidelines and the updated versions are based necessarily on non-optimal levels of evidence. Only 2% of the randomised controlled trials in pain relief study cancer pain directly [7].
Beyond trying to determine just how good the good and moderate relief is for the two-thirds of patients, there are two obvious problem areas, neuropathic pain and incident pain.
NEUROPATHIC PAIN
There are 2 extreme positions on opioid sensitivity. One suggests that opioid sensitivity is a relative phenomenon and therefore that any pain can be controlled by opioids provided that there is an adequate dose escalation and control of adverse effects [8]. The other extreme insists that some pains are intrinsically insensitive to opioids and that this insensitivity can be predicted from the clinical characteristics of the pain [9]. Nociceptive pain is thought to be sensitive to opioids while neuropathic pain is regarded as insensitive. If neuropathic pain shows an analgesic response with opioid then this has been attributed to mood improvement rather than to a direct effect on pain pathways [10].
Both extremes of this controversy are supported by a very small number of controlled trials each of which has methodological limitations. These studies have used either single doses [10, 11], infusions of different opioids [8, 9] or have measured pain without simultaneous assessment of adverse effects [9, 10, 11, 12]. The flaw with studies which use a single (fixed) dose or infusion rate is that they may underestimate responses in patients with previous opioid exposure. These patients may need more opioid to achieve analgesic effect than the opioid naive.
Using patient-controlled analgesia (PCA) with simultaneous nurse observer measurement of analgesia and adverse effects we gave two concentrations of morphine in a double-blind randomised cross-over fashion and compared the clinical responses produced by both concentrations of morphine [13].
The results did not support the assumption that neuropathic pains are always opioid insensitive. Half of the pains judged as neuropathic achieved a good response. Nociceptive pains, however, collectively showed a better analgesic response, because all of them achieved a good response in at least one of the sessions. No nociceptive pain had a poor response in this study.
Secondly, it had been suggested that the analgesic response of neuropathic pains to opioids can be explained by the changes in mood induced by the opioids [10]. When the results of patients with consistent responses were compared, changes in mood reflected changes in pain intensity and relief regardless of the clinical character of the pain, nociceptive or neuropathic. Mood improved when pain intensity decreased or pain relief increased. No patient had a change in mood in the absence of a change in pain intensity or pain relief, and patients with nociceptive pains in fact showed a greater change in mood than those with neuropathic pain. Therefore, the theory that relief of neuropathic pains by opioids is due to changes in mood was not supported by our findings.
INCIDENT PAIN
The problem with incident pain is that the analgesia necessary to control episodic incident pain is usually far more than is required when it is absent. The patient between bouts of incident pain may then suffer all the adverse effects of an 'overdose'. Optimal analgesic regimes should restore normal function. The reality, however, is that with sub-optimal regimes, or when the incident pain cannot be controlled satisfactorily despite an optimal regime, function and quality of life may have to be reduced to cope with the pain. In this delicate balance between adequate control of the incident pain and adverse effects between times the patient often opts to 'accept' the incident pain rather than to endure the adverse effects.
Classifying incident pain
The overlap in conventional use between the terms incident pain and breakthrough pain is unfortunate. Breakthrough pain describes an inadequate analgesic regime [14], and is therefore an operational definition of pain which is not controlled, but is 'breaking through' the analgesic regime. The regime may be adequate to control background pain but inadequate to control incident pain.
Incident pain is used commonly to describe pain on movement. Conventionally the widest definition is pain which comes on when the patient is not resting. This may be pain caused by deep breathing or coughing, or pain caused by walking, turning or lifting. These pains on activity or movement may, to an extent, be controlled by the patient, by not moving. Incident pain thus describes some characteristics of the pain, such as its relationship to coughing or movement, and describes those characteristics independent of the presence or absence of an analgesic regime. Breakthrough pain is one type of incident pain.
Complicating matters further there is a third kind of incident pain, which is an intermittent pain which can occur even when the patient is resting, and can occur with no known triggering process. The patient has no control over these pains. Complete description of the pain would also include whether or not the patient has background pain which is present at rest. The problem with restricting the definition of incident pain to pain related to movement or to activity is that excluding the intermittent, unpredictable pain excludes a considerable proportion of these difficult pains (see under prevalence below).
Figure 2 summarises the definition problems.
The simplest definition is that incident pain is characterised by episodic increases in pain intensity.
Another characteristic is the patient's ability to suppress or avoid the incident pain; the pain may be defined as "volitional" or "non-volitional" [14]. Volitional pain should be predictable.
Characteristics of incident pain
Pain on movement may be predictable, occurring each time the patient moves in a particular way. It may be brief or it may be prolonged. It may be acute, as a result of a recent change in disease or due to treatment. It may be chronic. These three axes, predictability, time course of the episodes and the chronicity of the problem, are shown in Figure 3.
How big a problem is incident pain?
Incident pain is a big problem both because it is common and because of the distress it causes the individual. The incidence and prevalence can only be estimated from small surveys. Portenoy and Hagen [14] reported on 90 patients at the Memorial Sloan-Kettering Cancer Center, and their findings are summarised in Figure 4.
Banning et al studied 200 consecutive referrals to the pain clinic at the Finsen Institute in Copenhagen [15]. Of the 184 patients whose pain they evaluated 172 had pain on movement, 144 had pain at rest and 124 had their sleep interrupted by pain.
From the Danish data most patients with cancer pain will have incident pain related to movement. Of the 131 patients with pain on movement who they re-evaluated 1 to 2 weeks after treatment 83 still had pain on movement, 20 with moderate intensity and 36 with considerable intensity. From the American survey (Figure 4) roughly half the patients had breakthrough pain despite an established analgesic regime. Both these reports are from tertiary care institutions, so that generalising to obtain incidence and prevalence data for the general population is invalid, because patients will be referred precisely because they do have pain. Within this selected population, however, it is a reasonable inference that incident pain is a major problem for most patients who have not started an 'adequate' analgesic regime, and that it remains a major problem for half of those who are established on analgesics.
How should incident pain be managed?
Restating the problem, it is that the doses of analgesics required to control the incident pain may be so high that toxicity results when the incident pain is absent. Pain relief in this situation is usually relief of symptoms rather than remedying the cause of the pain. Analgesics do not stretch to accommodate increased severity; increased doses are required, with concomitant risk of increased adverse effects. The questions then arise as to what changes (if any) should be made in our 'conventional' management strategies to cope better with incident pain, and what additional remedies should be considered.
The traditional way to manage cancer pain is illustrated by the WHO ladder (Figure 1). Two questions need to be addressed. The first is whether or not each of the three rungs of the ladder is able to control incident pain. The answer required for each rung is whether or not control is feasible, given adequate management of adverse effects. The incidence data suggests that, for a significant proportion of patients, it is not possible. It is also possible that better management of opioid adverse effects would allow higher opioid doses to be used with fewer adverse effects. An open study of methylphenidate suggests that this may be a useful approach [16]. The second issue is whether the incident pain (pain on movement or on coughing in the postoperative context) is simply the same pain at higher intensity or is something different; is it a quantitative or a qualitative difference?
Quantitative increase in pain on movement - evidence from postoperative pain
The evidence from postoperative pain suggests a quantitative difference between pain at rest and pain on movement; more analgesia is required to control the pain on movement, with the increased risk of adverse effects, but the pain can be controlled, at least by regimes which incorporate all three WHO ladder rungs, and particularly with the addition of local anaesthetic and steroids [17]. The studies from this Copenhagen group have shown that none of the individual rungs of the WHO ladder can achieve this degree of incident pain control on their own. It is only by using combinations that they have made progress. The ability to maintain pain intensity scores of zero on coughing for eight days after colonic resection is remarkable [17]. The regime used was methylprednisolone 30 mg/kg iv before surgery, thoracic epidural infusion of a combination of local anaesthetic and morphine, intrathecal (intraoperative) local anaesthetic and indomethacin 100 mg iv 8 hrly with oral indomethacin as required.
For incident pain in cancer the message must be that if the incident pain is a predictable quantitative increase of the pain at rest, then we should think of combinations of the rungs of the ladder, and of the use of local anaesthetic and steroids when that fails, by oral, subcutaneous [18] or epidural [19] routes. At first sight the Copenhagen regime appears to be way beyond what might be practical for cancer pain patients. The reality, however, is that epidural infusion of combinations of local anaesthetic and opioid is already being used outside hospital, and ten years ago few would have thought that practical. RCTs of combinations are notoriously difficult to conduct in any patient group, let alone epidural combinations in cancer pain patients, but they are badly needed. With an epidural catheter in place it is easy for booster doses to be given in response to episodic increase in pain intensity. The issue is not the technical feasibility, but whether it is an effective method and more appropriate than the alternatives.
Incident pain: qualitative increase in pain
The classes of drugs used commonly are antidepressants, anticonvulsants and steroids. The RCTs of these 3 classes have been in chronic non-cancer pain, and have focused on neuropathic pain syndromes, not on incident pain. The importance of these drugs in that incident pain which is qualitatively different from pain at rest is often of the neuropathic type. It is important then to know whether or not the pain responds to these classes of drugs.
The recent randomised controlled studies of antidepressants have reinforced the messages that first generation tricyclic antidepressants are more effective as analgesics in this context than the more selective antidepressants, that the relief and its duration do not depend on the quality of the pain (burning, shooting etc.), and that the relief can be obtained well within the first week [20, 21, 22, 23]. It is possible therefore to increase dose quickly to achieve an adequate trial of antidepressants without wasting time which is precious to the patient. Systematic review of anticonvulsants [24] showed similar benefit and risk levels to antidepressants [25]. There is little evidence on which to recommend one anticonvulsant rather than another. The oral (and intravenous) use of the local anaesthetics is based on good animal studies, but again we do not have adequate RCT evidence to recommend their use in man [26]. The use of steroids remains an enigma. In postoperative pain the analgesic effect of steroids has been shown. Widespread use of steroids in palliative care to control pains resistant to other therapy has not been subjected to the customary trials in non-cancer pain, because of concern about adverse effects. The use of steroids is therefore based on experience. The most recent development is the idea that ketamine, as a clinically available antagonist at the N-methyl-D-aspartate receptor complex, may be useful in this type of pain. Three recent studies support this idea, and we hope that full-scale RCTs will show whether or not this is a useful ploy [27, 28, 29].
The place of opioids in the treatment of this qualitatively different pain remains problematic. Doses of oral opioid adequate to control the incident pain may be excessive when the incident pain stops. This begs the question as to whether opioids can control this type of pain. The evidence suggests that, for some patients at least, they can [13], and that all patients should have an adequate trial of opioids. The problem remains that adverse effects may be overwhelming in the absence of the incident pain. If opioids could be given rapidly in response to the presence of the incident pain, were effective, and did not remain active when the incident pain had gone, then they would be appropriate.
Giving opioids as rapid 'boosters' in this context requires the use of routes of administration other than oral, because speed of onset of effect is too slow orally. Subcutaneous, intramuscular and intravenous routes can all provide faster speed of onset of effect than oral opioids, but with an inevitable increase in the logistic complexity. Bolus, infusion or patient-controlled analgesia (PCA) techniques are all possible [30], but being possible as alternatives to the oral route for cancer pain management in general does not necessarily mean more effective or more appropriate for incident pain. With new opioids such as remifentanil [31] which have a faster offset of effect than those available currently, it should be possible to test whether or not fast onset/fast offset opioids by injectable routes can improve incident pain management.
The Future
It is striking that there is so little data from controlled trials to guide our practice when the two incidence studies emphasise the importance of incident pain. Some thoughts for these studies are that the pain must be characterised well. Pain assessments need to be made at maximal pain, if predictable, and / or with the movement(s) which provoke maximal pain. We would suggest that the number of painful episodes should also be an outcome measure, with an indication of the severity of the episodes. A measure of typical pain intensity and typical pain relief [32] may be particularly valuable if the pain is unpredictable. Just as important are the design requirements of the studies [33]. Given that it is very difficult for any of us to do studies on substantial numbers of patients in this group, it surely is time that we combined forces to produce valid answers to worthwhile questions.
Red Herrings
Tolerance
Clinicians argue that tolerance to opioids, if it occurs, is driven by disease rather than by pharmacological tolerance. The first problem is that tolerance is used by some to mean any increase in dose, whereas others use it in the more technical sense of an increased dose required to produce the same effect.
It is ingenuous to argue that opioid tolerance does not occur in man - fleeting glimpses have been seen which echo the solid findings of both acute and chronic opioid tolerance in animal models [34]. The classic Houde experiments showed chronic tolerance when patients' analgesic response to a test dose was measured before and after chronic dosing [35, 36]. The pragmatic issues are whether the dose escalation required by some patients and producing difficult adverse effects could be avoided (safely) by blocking a tolerance-induced need for dose escalation, or (more simply) by changing opioid or indeed route of administration.
Addiction
Clinical pain management has emphasised a difference between the clinical and the laboratory pharmacology of opiates. It is as though there is one opiate pharmacology when the opiate is used to counteract pain, and another when it is not.
The respiratory depression which haunts prescribers in acute pain management is seen readily in studies of volunteers who are not in pain. For patients with opiate-sensitive pain, given appropriate doses of opiate, respiratory depression is minimal [37, 38]. The balance between pain and opiate respiratory effects is seen clearly in chronic pain. Patients maintained on oral morphine, with no clinical respiratory depression, and who then receive successful nerve blocks, must have their morphine dose reduced. Failure to reduce the dose will result in respiratory depression [39, 40]. One explanation is that the respiratory centre receives nociceptive input [41]. Presence of this input counterbalances any respiratory depressant effect of the opiate. Absence of this input, because of the successful nerve block, leaves the respiratory depressant effect of the opiate unopposed.
The clinical message is that opiates need to be titrated against pain. Doses higher than necessary for the relief of pain run the risk of respiratory depression. Prophylactic use of opiates, infusion without regard to pain experienced, doses greater than those required for analgesia (as in deliberate ITU use to facilitate ventilation of a patient), use for purposes other than analgesia (e.g. sedation), or use in non-nociceptive pain, thus all carry potential risk. Concern about respiratory depression should not inhibit the appropriate use of opioids, and that is to provide analgesia when the pain may reasonably be thought to be opiate sensitive. A postoperative patient still complaining of pain when the previous dose can be assumed to have been absorbed needs more drug.
Similarly the drug-seeking behaviour synonymous with street addiction is not found in patients after pain relief with opiates, either in childbirth, or after operations or after myocardial infarction [42]. Street addicts are not in pain. The political message is that medical use of opiates does not create street addicts. Medical use may indirectly increase availability to those who are already addicts, but restricting medical use hurts patients.
Adverse Effects
Specific adverse effects; metabolism
If an opiate has no specific advantage over morphine and has a specific disadvantage, such as a troublesome adverse effect not found with morphine, then there is little logic in choosing that drug in preference to morphine. Any drug which produced fewer side-effects than morphine, at a dose which provided the same degree of analgesia, would be an improvement. High dose fentanyl in cardiac anaesthesia causes less haemodynamic disruption than high dose morphine. For most clinically important side-effects there is no comparative evidence at equivalent analgesic doses to recommend any of the alternatives. Single-dose postoperative studies showed a higher incidence of nausea and vomiting with pethidine [43], and dysphoria (see below) with those mixed agonist-antagonists which have a relatively high affinity for kappa and sigma receptors [44]. As with non-steroidal anti-inflammatory drugs, the risk:benefit ratio may be different at equianalgesic dosing within the same patient [45], but we cannot predict these individual responses.
DYSPHORIA
Dysphoria occurs with all opiates, but the incidence varies widely between drugs. Pentazocine, butorphanol and nalbuphine have this potential [46]. The greater than 20% incidence with pentazocine and butorphanol contrasts sharply with the 3% incidence seen with other opiates. There is little sense in using an opiate which produces a higher incidence of dysphoria than morphine without any compensating advantage.
TOXIC METABOLITES
Pethidine is metabolised to norpethidine which is toxic [47]. It causes tremor, twitching, agitation and convulsions, and the incidence of these problems increases with multiple dosing and in the presence of impaired renal function [47, 48]. Morphine-3-glucuronide (M3G) may be a toxic metabolite. When this becomes problematic is still unclear.
ACTIVE METABOLITE
Whereas diamorphine [49] and M3G [50] do not bind to opiate receptors, 6-monoacetylmorphine, morphine, morphine-6-glucuronide (M6G) and normorphine do. Recent work on the metabolites of morphine has important clinical implications [51, 52]. Quantitatively the most important active metabolite is M6G, because M3G and M6G are the major metabolites of morphine in man [53, 54] and because of the greater potency of M6G compared with morphine. In rats, M6G is 45 times more potent than morphine intracerebrally and nearly 4 times more potent subcutaneously [55]; intrathecal injection gave potency ratios been 10 and 20 [56]. M6G may contribute substantially to the analgesic effect of morphine, in both single and repeated doses [57, 58, 59].
Diamorphine is a classical pro-drug. Without analgesic activity itself, it initiates the "cascade" into the active 6-monoacetylmorphine, morphine and M6G. Because of the speed of these reactions, there is no clinical advantage over morphine by oral or intramuscular routes, either in terms of greater analgesic efficacy or of improved mood [60, 49]. This does not exclude advantage from intravenous, spinal or other routes.
PATHOPHYSIOLOGY
Unexpected degree and duration of effect can be obtained with morphine, codeine and dihydrocodeine when they are used in patients with severely impaired renal function [61]. Cumulation of M6G is the probable explanation of this phenomenon. Prolonged respiratory depression has been reported in man in association with negligible plasma concentrations of morphine but with very high concentrations of M3G and M6G [62]. Glucuronidation of morphine is altered little in hepatic failure [63], but in pre-coma kinetics [64] and dynamics [65] are altered.
Problems should arise only if a fixed-dose schedule is used without taking account of renal function, or without adequate titration against pain intensity. Drug doses should be decreased markedly if creatinine clearance is less than 30 ml min-1. With less severe renal dysfunction the potential problem emphasises the need for careful titration, remembering that renal function deteriorates with advancing age.
NAUSEA AND VOMITING AND CONSTIPATION
It has been very difficult to obtain data on adverse effect incidence from randomised studies. The recent paper by Moulin et al [66] showed that a third of the forty patients experienced adverse effects under this heading.
Prescribing Opioids in Chronic Non-cancer Pain
The argument that patients in pain who do not have cancer should not be given opioids is of great concern. If opioids provide pain relief for a patient, and there is no other effective remedy, who is to decide that the patient should be denied pain relief and for what reason? Obviously not all patients with non-cancer pain should be treated with opioids. There are, however, of a small number of patients in whom opioids are the only effective remedy. It is the right of these patients to obtain effective relief, and of their doctors to prescribe such relief for them, which should be upheld.
The reasons given commonly for withholding opioids in non-cancer pain include concern for the patient and concern for the community. The concern for the patient is that opioids may make the patient a drug addict and that opioids may have other adverse effects on the patient's health. The concern for the community is that opioid prescription to this patient group will perforce lead to an increase in street addiction. There is no evidence that patients with chronic non-cancer pain treated with opioids become addicts or that their health is impaired. There is no evidence that such medical availability has any impact on street addiction. Indeed there is evidence to the contrary. When oral opioids began to be used in Sweden to control cancer pain, this increasing medical availability had no impact at all on street addiction [67].
A recent review of the evidence for the treatment of cancer pain [68] is equally valid for opioid prescribing in other pain contexts. The 45 authors, 12 pharmacologists, 10 physicians, 8 pain clinic doctors, 7 psychologists, 3 lawyers, 3 experts from drug addiction and 2 experts in biomedical ethics, could find no medical, psychological, legal or ethical reason to withhold opioids in cancer pain. What then is the difference in pain not due to cancer? The obvious difference is in potential duration of treatment. The longitudinal surveys published to date suggest no difference between the two populations of patients.
The proportion of patients with chronic non-cancer pain for whom opioids might be considered is small, because not all of these patients obtain relief from opioids, some patients are psychologically unsuitable, some patients do not want to take opioids and other doctors involved in the patients' care may oppose opioid use. For those in whom we are considering opioid treatment we use the following guide-lines:
1. all other relevant treatments have failed
2. the pain is shown to be relieved by opioids
3. the patient, after clear explanation and discussion with family and family practitioner, is willing to take opioids
4. other doctors involved in the patient's care agree with opioid prescription
5. appropriate follow-up
Those who oppose opioid prescription should make their motives clear. There is no evidence to support the reasons which they advance. In the absence of such evidence we hope that the rights of that small number of patients for whom opioids are the only effective remedy to obtain relief, and the right of the doctor to prescribe, will be protected.
Clearly it is neither necessary nor desirable to subject patients with terminal disease who are obtaining effective relief from opioids to such a battery of tests. Problems do arise, however, in which this approach may help. The first is the general case when relief is ineffective and it is unclear to the clinician whether or not better relief can be achieved by a higher dose without intolerable or unmanageable adverse effects. This is equivalent to the question 'Can a poor or moderate response be converted to a good response by using a higher concentration?' The second is specific to the vexed question of opioid prescription in chronic non-cancer pain. Such prescribing is viewed as potentially dangerous for both the patient and society [69, 70], although published evidence suggests that neither belief is valid [68]. Opioids should be considered for patients for whom there is no other effective remedy, in whom opioids are effective, and given that both the patient and the patient's doctors agree [71].
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