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Acute pain management in opioid-tolerant patients: a growing challenge.

Opioid tolerance occurs in individuals prescribed opioids for long-term management of either chronic non-cancer pain (CNCP) or cancer pain and those who are, or have been, problematic or illicit users of opioids, some of whom may be enrolled in opioid substitution programs. There may be considerable overlap between these two groups: those prescribed opioids for relief of pain may misuse these and other drugs (1), and individuals with an opioid addiction may also experience CNCP or cancer pain (2). Acute pain presentations in this population, in addition to elective surgery or medical illness, include surgery for CNCP and cancer as well as for the complications of drug abuse (e.g. trauma, infection).

This review examines opioid prescribing trends, considers the mechanisms underlying opioid tolerance and opioid-induced hyperalgesia (OIH) and their clinical implications, and discusses acute pain management options in opioid-tolerant patients. Most of the relevant literature relates to surgical inpatients and the focus is therefore on the management of postoperative pain. However, the information can be extrapolated to other acute pain situations.

EPIDEMIOLOGY OF OPIOID USE

From 1989 to 2009, global use of prescription opioids more than trebled (3). Morphine use rose from 6.5 to 19.6 tons between 1989 and 1998 and then to 41.8 tons in 20 094. Consumption of oxycodone increased slowly from 1989 to 1998, remaining at less than 10 tons worldwide, but escalated dramatically between 1998 and 2009 to reach 77 tons (4).

In 2009, the USA (with 5.1% of the world's population) was the main consumer of these opioids, accounting for 56% of global morphine and 81% of global oxycodone use4. Australia and New Zealand together (0.4% of the world's population) made up 2.8% of total morphine consumption and Australia alone accounted for almost 2% of oxycodone use. Worldwide, Austria had the highest morphine consumption per person per day (where it is used for both analgesia and opioid substitution programs), USA was third (behind Canada), New Zealand was seventh and Australia was eighth. For oxycodone, the USA had the highest per person use with Australia third. New Zealand's overall oxycodone use was insignificant (4).

In Australia, between 1991 and 2007, total morphine base supply (i.e. the quantity of all formulations in kilograms per year) increased four-fold (5). This included a 40-fold growth between 1990 and 2006 in oral morphine, almost all as slow-release (SR)--also known as controlled-release--preparations (5). Over the same period, total oxycodone base supply rose ten-fold--most of this increase coincided with the introduction of SR oxycodone in 19995. In both countries, the increased consumption has far exceeded the rate of population growth (5).

Prescribing patterns

Precise details of opioid prescribing in Australia are difficult to obtain, as neither indication for treatment nor quantity of opioid dispensed are recorded. However, there has been a significant rise in the total number of opioid prescriptions issued under the Australian Pharmaceutical Benefits Scheme (PBS) (6). In 1992, there were nearly 2.4 million (excluding methadone and buprenorphine for the pharmacotherapy of opioid addiction) (6) for a population of about 17.5 million (7). In 2007, despite only modest population growth to just over 21 million7, the number of opioid prescriptions had escalated to almost seven million (6). These figures are an underestimate as they do not include non-PBS prescriptions (6).

From 1992 to 2007, the number of PBS-listed opioids grew from four to eight and the number of formulations from 11 to 706. Morphine prescriptions rose until 2000 and changed little until 2004, after which they declined slightly. In contrast, oxycodone prescriptions slowly increased until 2000 and then rapidly escalated, coinciding with the PBS listing of SR oxycodone. Prescriptions for codeine peaked in 1999 then declined steadily, whereas those for tramadol grew rapidly after its introduction in 2000 until 2004 and then reached a plateau (6). In 2006, fentanyl prescription started to increase (6), coinciding with PBS approval of transdermal fentanyl patches for management of CNCP (8).

In New Zealand, the variety of preparations has also increased. In May 2009, the Pharmacology and Therapeutics Advisory Committee added buprenorphine to the pharmaceutical schedule which already included codeine, dihydrocodeine, fentanyl, methadone, morphine, oxycodone and pethidine (9). As in Australia, prescribing data from New Zealand are limited. However, the number of prescriptions for morphine dispensed at community pharmacies increased by over 50% from 1996 to 2006 (10).

Prescribing trends in the USA are similar to those reported in Australia and New Zealand; between 1997 and 2007, retail sales of morphine and oxycodone increased more than two- and eight-fold respectively (11).

Chronic non-cancer pain

The estimated prevalence of CNCP in adults in Australia and New Zealand is between 5 and 20% (5,12,13). This is similar to other developed countries and is predicted to increase as the population ages (5). In the past, the widely held medical view was that the long-term use of opioids for management of CNCP invariably led to tolerance and that there was an unacceptable risk of addiction (14). More recently, at least in the developed world, use of opioids for CNCP has become more common and major professional bodies have developed prescribing guidelines (15,16). However, evidence for the efficacy of long-term opioids in those with CNCP remains conflicting and generally of low quality (17,18). Opioid use for CNCP is being reexamined in light of increasing awareness of potential adverse consequences including prescription opioid abuse and diversion (11,19). An 'universal precautions' approach along with appropriate risk assessment and management has been recommended (20-22).

Cancer pain

It is predicted that, by the age of 85 years, one in two Australian men and one in three Australian women will have been diagnosed with cancer (excluding non-melanoma skin cancers) (23). Although not universal in those with cancer, pain is a presenting symptom in 20 to 50% and is experienced by up to 90% in the advanced stages of disease (24). Risks related to long-term opioid use include declining efficacy over time and neurobiological effects that may enhance pain or adversely alter cancer progression (24). Therapeutic advances have improved longevity. It has been recommended that pain in cancer survivors is managed using a similar approach to that used in CNCP (1).

Opioid substitution programs

Methadone and buprenorphine substitution are well accepted treatments for opioid addiction (5). Both drugs, the latter either alone (Subutex[R], Reckitt Benkiser Healthcare Ltd, UK) or combined with naloxone (Suboxone[R], Reckitt Benkiser Healthcare Ltd, UK) designed to deter intravenous injection, are available in Australia and New Zealand (25,26).

Commenced in Australia in 1969, methadone maintenance therapy (MMT) was formally recognised in 1985 as appropriate pharmacotherapy of opioid addiction (25). Subutex, introduced in the 1980s, was PBS-listed in 2000 and Suboxone in 2005 for use as buprenorphine maintenance therapy (BMT) (27). From 1998 to 2009, the number of Australians receiving MMT or BMT increased from 24,657 to 43,445 (25).

Many patients enrolled in opioid substitution programs report ongoing opioid or polydrug abuse. In Australian post-marketing surveillance studies of Suboxone, approximately one-quarter admitted to injecting their dose at least once in a six-month period (28); one in five acknowledged occasionally selling or giving away their medication and a small number were identified as 'doctor shoppers'. Self-injection was most prevalent in those using Subutex and less common with methadone and Suboxone (28).

Illicit opioid use

In 2008, it was estimated that illicit opioids (i.e. opium, heroin or other opioids that were not prescribed for the individual or bought legally) were used by 12 to 22 million people worldwide, representing 0.3 to 0.5% of those aged 15 to 64 years (3). From 1995 to 2009, despite a 13% fall in 2008/2009, worldwide illicit opium production increased by almost 80% (3). This is similar to the rate of global population expansion and use prevalence has thus remained relatively stable. However, the pattern of illicit opioid use has changed with the illicit use of prescription opioids increasing (3).

As licit (i.e. prescribed for the individual) opioid use has increased in the USA, so has its abuse (29). The United States Food and Drug Administration has responded to the 'societal crisis' of prescription opioid abuse by increasing regulatory controls and developing risk evaluation and mitigation strategies for long-acting opioids as part of approval processes (29).

In Australia, illicit drug use is monitored by the Australian Institute of Health and Welfare. Their National Drug Strategy Household Survey has been conducted every two or three years since 1985. Comparison of the most recent report (2007) with that published in 2004 shows that prevalence of illicit use of heroin and methadone remained relatively stable, while illicit use of some other opioids (including morphine) decreased (30). Overall prevalence may have fallen slightly, with the total number of individuals illicitly using opioids decreasing from just over to just under 600,000 (30). These figures are probably an underestimate as they rely on self-report and do not include the homeless or the institutionalised.

The Australian Illicit Drug Reporting System is designed to identify emerging trends in illicit drug use among injecting drug users (IDU). Information is obtained in large part from a survey of those who had injected drugs at least monthly during the six months preceding the interview. Between 2001 and 2009, heroin was the drug of choice in 48 to 58% of IDU compared with just 5 to 10% for morphine (31). In the same period, heroin was also the drug injected most commonly in the month prior to interview (27 to 47% of IDUs compared with 6 to 19% for morphine). No time-related trends were obvious.

In 2009, 44% of the IDU sample had 'used' morphine (both licit and illicit, predominantly injected) in the six months prior to interview, ranging from 24% in South Australia to 82% in Tasmania (31). Nationally, however, between 2000 and 2009 IDU use of morphine remained relatively stable, although significant yearly and regional fluctuations occurred (31).

Oxycodone use by IDUs is more difficult to track over time because of changes in methodology. Prior to 2005 it was included in the Australian Illicit Drug Reporting System reports under the category 'other opioids' (which also included Panadeine Forte[R], Sanofi-Aventis Australia, Macquarie Park, NSW, codeine, opium and pethidine) and no distinction was made between 'licit' and 'illicit' oxycodone (31). In 2002, this group of drugs as a whole was used by 22%, and injected by 8%, of IDUs (32). In 2005, because of concerns about diversion and unsanctioned use, oxycodone was classified separately (31). In that year, use by IDUs of licit and illicit oxycodone within the prior six months was 5 and 18% respectively (33). By 2009, the rate for licit use was unchanged but 30% now reported illicit oxycodone use (injected by 93% of this group) (31). This is reflected in data from the King's Cross Medically Supervised Injecting Centre where, since late 2006, prescription opioids have also been more commonly injected than heroin (34).

New Zealand's illicit drug market and use pattern differ. Geographical isolation and successful policing have limited heroin availability. Misused/injected opioids are more commonly prescription drugs such as morphine or methadone or 'over-the-counter' drugs converted to 'home bake' (codeine which has been refined to produce morphine/diamorphine) (35). From 1990 to 2006 the prevalence of opioid abuse remained stable at between 0.4 and 0.6% (36,37). In 2008, there was a sharp increase to 1.1% for uncertain reasons (3).

Serious adverse effects following prescription opioid abuse/misuse

In the past decade, hospital presentations as a result of serious adverse effects following misuse/ abuse of prescription opioids have increased. In the USA between 2004 and 2009, the number of emergency department presentations increased by almost 90% (38). The largest increases were for cases involving oxycodone (242.2%) and hydrocodone (148.3%) while presentations resulting from misuse of cocaine, marijuana and heroin fell by just 1.8% (38). In Australia, the number of patients treated for poisoning by opioids other than heroin or methadone increased almost three-fold (from 605 in 1998/1999 to 1700 in 2007), while poisoning from heroin fell (1712 to 446) (39).

In the USA, both opioid prescription rates and opioid-related fatalities have increased, raising concerns about causation (5,11). Examples include oxycodone (associated with 14 deaths in 1998 and 1007 in 2005), morphine (82 and 329 respectively), fentanyl (92 and 1245) and methadone (8 and 329) (5). There is also evidence from the USA that among those prescribed opioids for CNCP, the higher the dose prescribed the greater the risk of opioid-related fatality (40). The correlation between overall oxycodone use and oxycodone-related mortality has also been reported in Victoria, Australia (Figure 1). In 2000 there were four coronial cases in which oxycodone was detected; by 2009 this had increased to 97. Over the same period oxycodone supply to the state increased nine-fold (41).

[FIGURE 1 OMITTED]

MOLECULAR BASIS OF TOLERANCE AND OPIOID-INDUCED HYPERALGESIA

Tolerance describes the decrease in effect following repeated administration of a drug that can be overcome by an increase in dose (right-shifted dose-response curve). Previously, in patients taking long-term opioids without disease progression, a decrease in the effect of these drugs has usually been attributed to the development of tolerance. However, it is now thought that administration of opioids can also lead to OIH, an enhanced response to a stimulus that is normally painful (42), which will also reduce the analgesic effect. It is important to recognise that opioid tolerance and OIH are distinct but likely overlapping phenomena, whereby tolerance causes an increase in [ED.sub.50], but OIH leads to a decrease in the response at dose zero ([E.sub.0]-baseline) (43).

Evidence for OIH comes mainly from human volunteer studies and small clinical studies in individuals taking long-term opioids. To date, the strength of that evidence has been modest and limited (44,45). The major difficulty in documenting clinical evidence of OIH is that any increase in pain in patients taking long-term opioids could also be due to ongoing tissue damage (e.g. from progression of cancer) or opioid tolerance (46).

In studies using experimental pain induction, subjects on MMT are hyperalgesic and have a much lower tolerance to the cold pressor test compared with control groups (47-49). Similar studies have been reported in subjects on BMT (50,51) and morphine-maintenance (49). In addition, in those receiving morphine or methadone for CNCP, cold pressor tolerance times were almost half those of age- and gender-matched controls, but similar to those on MMT (52). Other studies have addressed the onset of OIH (occurred within a month after starting oral morphine) (53) and its resolution (takes at least one month) (54).

There is limited evidence for rapid development of OIH. After surgery, pain scores and opioid requirements were increased in patients given higher doses of fentanyl (55) and remifentanil (56) intraoperatively. However, these results, based on increased pain scores and opioid consumption only, could indicate either OIH, tolerance to opioids or a combination of both. A formal diagnosis of OIH would require quantitative sensory testing, before and after surgery (57).

In the experimental pain setting, rapidly developing OIH has been reported in healthy subjects receiving remifentanil (58,59). A study investigating tolerance, however, showed no significant difference before and after "two different but clinically relevant doses" of remifentanil (60).

Mechanisms underlying tolerance and OIH

The mechanisms underlying tolerance and OIH are still not fully understood. However, it seems clear that the neurobiology is complex and multifactorial (61). Tolerance may involve not only alterations in receptor regulation, desensitisation and internalisation, but other mechanisms including glial activation (62). For OIH, proposed mechanisms include a role for glutaminergic activation (also implicated in tolerance), altered opioid intracellular signalling involving G protein-coupled receptor switching, a role for substance P and neurokinin 1 (NK-I) receptors and spinal dynorphin and, finally, increasing evidence implicating Toll-like receptor (TLR) signalling and glial cells.

Glutaminergic activation

The main mechanisms by which opioids trigger the glutaminergic system involve glutamate-associated activation of n-methyl-d-aspartate (NMDA) receptors, inhibition of glutamate transport reuptake and calcium-regulated intracellular protein kinase C (63). In animals, the NMDA receptor antagonist, ketamine, has been shown to attenuate the development of OIH when given systemically or intrathecally (61). In humans, S-ketamine blunted remifentanil-induced hyperalgesia caused by intradermal electrical stimulation (58,59) and low dose ketamine prevented remifentanil-induced postoperative wound hyperalgesia (64).

Spinal dynorphin

During chronic pain, spinal dynorphin A increases. This acts on bradykinin receptors causing a switch in the G protein to a stimulatory G protein (G[alpha]s). This ultimately causes an increase in intracellular calcium levels, release of the excitatory neuropeptide calcitonin gene-related peptide and potentiation of pain and neuronal hyperalgesia (65). Whether exogenous opioids are able to perform similarly remains unclear.

Substance P and NK-1

In animals, chronic morphine increased substance P and NK-1 receptor expression in the spinal dorsal horn. This was associated with hyperalgesia, could be reversed using NK-1 antagonists and was not seen in NK-1 receptor knock-out mice (66).

Mu receptor G protein switching

In animals, acute hyperalgesia elicited by low dose morphine can be blocked by an ultra-low dose of naloxone (67). At such low doses, it is believed that morphine activates Gas which induces hyperalgesia. Naloxone binds to a scaffolding protein, filamin A, which interacts with the mu-opioid receptor to disrupt the morphine-induced mu-opioid receptor Gas coupling (68).

Opioids, glial signalling and pro-inflammation

A newer mechanism has recently been proposed to explain, at least partially, OIH and tolerance. Glia, the immune-like cells in the brain and spinal cord, have a number of metabolic functions, and molecules released by glia can interact with neurons providing a glia-neuron communication (69). Specifically, TLRs expressed on glia and opioids independently activate a TLR4 signalling cascade and consequently activate glia. Although opioids bind to the mu-opioid receptor on neurons, leading to their analgesic and other effects, they also dock onto glia via TLR4. Docking of opioids to TLR4 causes intracellular signalling that results in the expression of a number of pro-inflammatory mediators, especially IL-1[beta] and IL-6. These cytokines bind to their receptors on neurons and are pro-nociceptive. IL-1[beta] increases extracellular glutamate by down-regulating the glutamate transporter GLT-1. It also phosphorylates the NMDA receptor leading to an increase in channel opening, allowing an influx of calcium which causes increased nitric oxide and PGE2, amplifying the excitability of pain projection neurons (69,70). Blockade of opioid-induced TLR4 signalling through genetic and pharmacological methods enhanced opioid analgesia and attenuated the development of opioid analgesic tolerance and hyperalgesia (71).

This effect of glial activation by opioids has the potential to provide a unifying mechanism through which the final pathway of neuronal sensitisation leads to both OIH and opioid-induced tolerance. Caution is required as the mechanism, although elegantly delineated from animal studies, has not been verified in humans.

PRINCIPLES OF ACUTE PAIN MANAGEMENT

The main aims of management in opioid-tolerant patients are to promote adequate perioperative analgesia, prevent drug abstinence (withdrawal) syndromes, and assist with any related social, psychiatric and behavioural issues. Management should commence at the time of preoperative assessment, often prior to admission, and include appropriate discharge planning.

A collaborative, interdisciplinary approach, working closely with other treating clinicians in both the hospital and community, in order to maintain continuity of patient care, is particularly important (72). Although treatment in many patients is relatively straightforward, assessment and management can be time-consuming in those with more complex issues. The anaesthetist/pain medicine specialist is also in a position to ensure that individual and staff expectations about acute pain management are realistic, that risk management strategies are put in place and that all members of the team (including the patient) are working towards common goals.

Evidence relating to the perioperative management of the opioid-tolerant patient is limited and largely based upon case reports, case series and expert opinion. While some treatment strategies may be extrapolated from studies in the opioid-naive, there are self-evident limitations to this approach. While the principles outlined in the following sections apply to anyone who is opioid-tolerant and has acute pain, most of the relevant literature relates to surgical inpatients. The focus will therefore be on the management of acute pain in opioid-tolerant patients admitted for surgery.

PREOPERATIVE MANAGEMENT

Identification of opioid tolerance is an important first step. If overlooked at the time of preoperative assessment, it may become apparent only when postoperative pain is difficult to control. In addition to a routine preoperative history, targeted information should be sought (Table 1). Documentation of all usual drugs and doses is especially important if good postoperative analgesia is to be achieved and withdrawal from drugs such as opioids, benzodiazepines and alcohol avoided. A non-judgemental approach, along with an explanation that knowledge of all drugs used (prescribed and illicit) is necessary in order to provide good pain control, will improve information gathering.

Doses of relevant prescribed drugs must be verified (73,74), either from the dispensing label on the prescription packaging or by contacting the general practitioner, dispensing pharmacist, drug treatment centre or appropriate regulatory authority. Dose verification may not be possible in emergency settings or after-hours. In this case, as a temporary measure, and in order to avoid the risk of opioid withdrawal, the reported daily opioid amount can be given in two to four divided doses, with response monitored closely--using repeated assessment of a patient's level of sedation and respiratory rate (see later comments regarding sedation and respiratory rate as clinical indictors of early respiratory depression)--after each dose until confirmation is obtained (74). In some cases, admission to a high-dependency setting may be considered, especially if the reported 'usual' dose is high. In addition, if there is doubt about whether the verified dose is being taken in full (for example, if there is concern about diversion of any part of the prescribed amount), it may be prudent to give a portion of the reported dose and repeat this over the day as needed (if the patient is not sedated) (75).

The plan for pain relief should consider patient preferences, past experiences (76) and long-term management plans. Reassurance of patients that acute pain management is a priority is often required and that adequate analgesia, although potentially more difficult than in the opioid-naive, is not precluded by previous bad experiences of pain management or opioid addiction (77-79).

All regular opioids and other drugs prescribed for pain management should be taken or administered on the day of surgery, even if the patient is fasting, unless there is a specific reason for not doing so (e.g. non-selective nonsteroidal anti-inflammatory drugs [NSAID] if perioperative bleeding is a concern). Those enrolled in an opioid substitution program, who are to be admitted on the day of surgery, may be able to arrange a 'take-away' dose that can be self-administered preoperatively.

INTRAOPERATIVE MANAGEMENT

If the prescribed long-term opioid has not been taken preoperatively or if the surgery is prolonged, intraoperative doses should be adjusted accordingly. Opioid-tolerant patients may have much higher than expected additional intraoperative opioid requirements. However, assessment of adequate opioid administration is difficult. In spontaneously breathing patients, opioid titration to respiratory rate is a reasonable guide. With a general anaesthetic-relaxant technique, re-establishing spontaneous ventilation towards the end of anaesthesia and titrating opioid to achieve a respiratory rate of eight to ten breaths per minute may assist. Particular care should be taken to ensure adequate intraoperative loading with a longer acting opioid when using an infusion of remifentanil.

Opioid-tolerant patients are at increased risk of awareness (80) and depth of anaesthesia monitoring (with cautious interpretation of results, especially if using ketamine) may be indicated (81). Care should be taken with the placement of warming devices in those with transdermal drug delivery systems, as the heat may accelerate drug release (82).

POSTOPERATIVE MANAGEMENT

Effective management of acute pain is often more difficult in opioid-tolerant patients compared with their opioid-naive counterparts. Analgesic drugs and techniques may also be required for longer periods (83) and involve significant deviations from 'standard' treatment protocols (84). In all patients, appropriate assessment and monitoring is needed so that analgesia can be individualised. For those with preexisting pain, it may be reasonable to differentiate the 'new' acute pain from the 'usual' site of pain and explain that the primary focus of management will be the former.

Assessment and monitoring

Postoperative pain scores may be higher and decrease more slowly than in the opioid-naive (83,85). Interpretation of elevated pain scores can be difficult, particularly if considered in isolation, and comparison with pre-existing ('usual') pain scores can help. Dynamic measures of pain (ability to deep breathe, cough and ambulate) should also be assessed (86). These can be quantified using the Functional Activity Score (87), where 'A' is no limitation of relevant activity due to pain (relative to baseline), 'B' is mild limitation and 'C' is severe limitation. Persistently high pain scores as well as misplaced assumptions about 'pain patients' and 'addicts' can hinder assessment and diagnosis. If pain scores escalate or fail to decline in the postoperative period, other reasons for pain (e.g. surgical complications) should be considered.

If opioid tolerance has not been identified preoperatively, it should be suspected if the following triad is present after surgery: elevated pain scores, high opioid use and low incidence of side-effects (apart from sedation) (83). Identification of opioid-tolerance can be even more difficult in intensive care settings, in part because of competing clinical goals, particularly with urgent admissions or because of a patient's inability to communicate (e.g. due to injury or sedation for ventilation) (88). Strategies that may help include obtaining history from family, friends and usual doctors, consultation with specialist services and anticipation of illicit drug use in certain settings (e.g. trauma) (88).

Monitoring for the onset of opioid-related side-effects is also required. While tolerance to the analgesic effects of opioids, as well as many of their side-effects including nausea, sedation and respiratory depression, occurs reasonably quickly (89), it is possible, especially if opioid doses are significantly and rapidly escalated above baseline levels, that respiratory depression may still develop.

In one study, opioid-tolerant patients using patient-controlled analgesia (PCA) were less likely to report nausea, vomiting and pruritus than opioid-naive controls (83). However, the incidence of moderate or severe sedation in the opioid-tolerant group was 50.3% compared with 19.0% in the control group. Anxiolytics were more commonly given to the opioid-tolerant (17.5% compared with 0.7% of controls), but no significant correlation with sedation was found. Despite this, the risk of central nervous system (CNS) depression is higher when opioids are combined with other CNS depressants, such as benzodiazepines and clonidine (74). Therefore, as with all patients given opioids for the management of acute pain, monitoring must include indicators of excessive dose and adverse effects. Respiratory rate and level of sedation (known to be a better clinical indicator of early respiratory depression than a decrease in respiratory rate (84,87)), should be assessed on a regular basis irrespective of concurrent sedative administration.

Effective analgesia

Opioids and tramadol

As with opioid-naive patients, opioids are the mainstay of effective management for moderate to severe acute pain. However, the amount of opioid needed in addition to usual long-term opioids may be much higher. After a variety of surgical procedures, first 24-hour PCA morphine requirements were, on average, three times greater in the opioid-tolerant compared with opioid-naive controls (83). However, there is great variability in opioid requirements and it is worth noting that in some opioid-tolerant patients, opioid requirements were similar to those who were opioid-naive.

When moderate to severe pain is anticipated, PCA is a useful way of delivering additional opioids as it allows self-titration, minimises the risk of under-dosing (with appropriate review and adjustment) and reduces opportunities for conflict with and demands on ward nursing staff. There is no simple method for predicting the total dose that will be required by those with opioid-tolerance.

Use of individual preoperative 'fentanyl challenge', given to the point of respiratory depression followed by pharmacokinetic modelling to predict intra- and postoperative opioid requirements, has been used to calculate PCA bolus dose and background infusion rate (90). Alternatively and more simply, calculation of the PCA bolus dose can be based on the dose of long-term opioid already being taken (84,91). Use of PCA background infusions is not usually recommended in the opioid-naive, because of the increased risk of respiratory depression (92). However, in opioid-tolerant patients, this may be an appropriate way to deliver the equivalent dose of long-term oral opioid if oral administration is not possible (84). Opioid-tolerant patients may also require more frequent PCA prescription changes (93) and the care of an acute pain service for longer (83,93).

In those with CNCP or cancer pain taking opioids on a long-term basis, the relative roles played by opioid-tolerance and OIH are unknown, but likely to be interrelated (43,89). If inadequate pain relief is thought to be due to OIH, a reduction in opioid dose may improve analgesia (43,89). However, no such studies have been performed in the acute pain setting where, if pain increases and after there has been a thorough assessment to exclude other causes of this increase, the initial response should be to escalate the opioid dose aiming for effective pain control without adverse effects (74). If pain does not respond to this approach, then acute neuropathic pain or OIH may be suspected and use of additional non-opioid agents and opioid rotation (or reduction) considered.

Tramadol is an attractive choice of analgesic in some opioid-tolerant patients because of its lower abuse potential. However, using tramadol alone may not prevent opioid withdrawal or provide sufficient analgesia (74).

Non-opioid analgesic agents

In opioid-naive patients, paracetamol, non-selective NSAIDs and COX-2 selective NSAIDs were opioid sparing, although the decrease in morphine use was small--just 6 to 10 mg in 24 hours (94). A decrease in postoperative nausea and vomiting was seen only with use of non-selective NSAIDs (94). Despite a lack of evidence in the opioid-tolerant, if there are no contra-indications, it seems reasonable to include these drugs in treatment regimens.

Regional analgesia

Regional analgesia may be useful in the early postoperative period as it theoretically removes the need for additional systemic analgesia. However, neuraxially administered opioids may not prevent opioid withdrawal and additional systemic opioids are often required (72,74). In the absence of clear evidence about the use of larger than 'standard' doses of intrathecal and epidural opioids in opioid-tolerant patients, it may be difficult to estimate an appropriate or safe dose. In some institutions, policies dictate that epidural opioids should not be used concurrently with systemic opioids, because of the increased risk of respiratory depression; this may or may not apply to the opioid-tolerant.

Attenuation of tolerance and OIH

NMDA receptor antagonists

In opioid-naive patients, concurrent use of low dose ketamine with opioids improved analgesia and was opioid-sparing, with minimal or no side-effects related to ketamine (95,96). Given in conjunction with PCA opioids (not necessarily added to the PCA opioid solution), it also reduced the incidence of postoperative nausea and vomiting (95).

Ketamine may also be useful when given in addition to opioids for the management of acute pain in the opioid-tolerant (74,84). The effect of ketamine in opioid-tolerant patients undergoing spinal surgery has been the subject of two randomised controlled trials. In one, intraoperative ketamine (bolus dose followed by infusion to skin closure) reduced pain and opioid requirements in the first 48 hours after surgery as well as at six weeks (97). In the other study, ketamine, given on induction and followed by an infusion for 24 hours, improved postoperative analgesia, but PCA hydromorphone use was not significantly reduced (98).

Reported infusion regimens for ketamine vary. However, initial rates of 100 to 200 mg/24 hours or 0.1 mg/kg/hour have been suggested (84). As the elderly may be more sensitive to the effects of ketamine, lower doses may be appropriate (74). Due to very variable PCA opioid requirements in the opioid-tolerant patient, a fixed ratio of ketamine to opioid may lead to a higher incidence of side-effects such as dysphoria and hallucinations. It is therefore recommended that ketamine is administered separately at a fixed rate, rather than included in the PCA opioid solution (84).

Naloxone

Ultra-low dose naloxone has reduced opioid tolerance in animal studies (99-101). It has also enhanced buprenorphine analgesia in experimental pain studies in humans (102). Evidence from the acute pain setting is limited and not specifically related to opioid-tolerant patients. When given concurrently with PCA, naloxone has been reported to have no effect on postoperative pain relief (103,104) and to increase pain (105), although in 'ultra-low' doses it may reduce the incidence of opioid-related nausea and pruritus (104). Therefore, there is currently no good evidence to support the use of low dose naloxone for this indication.

Opioid rotation

Opioid rotation ('switching'), changing from one opioid to another, is widely used in palliative care practice to improve analgesia and reduce opioid-related side-effects. Evidence for its efficacy consists mainly of case series and expert opinion (106,107). Putative mechanisms include incomplete opioid cross-tolerance, differing receptor activity and the presence of active metabolites in some cases. Using an opioid that is different from the preadmission opioid may be a useful strategy for acute pain management (91).

Opioid rotation is undertaken by converting opioid doses using published equivalence tables and, in view of incomplete cross-tolerance, commencing with 30 to 50% of the calculated equianalgesic dose. Opioid conversion ratios are complex and influenced by the switch direction (108,109), pharmacokinetic factors (including bioavailability and active metabolites), variable opioid and nonopioid receptor activity (108) and pain type (110). Many conversion tables represent an oversimplification of the process of changing opioids and it is critically important that they are not used as 'recipe books' (108).

In rodents, studies examining combinations of oxycodone and morphine (111) and methadone and morphine (112) have supported the hypothesis that mixtures of opioids are synergistic, leading to better pain relief and fewer opioid-related side-effects compared with equianalgesic doses of each opioid given alone (113). This may be a result of individual opioids interacting with different opioid receptor subpopulations or modulating mu-opioid receptor signalling in different ways (113). Limited evidence of benefit exists in the acute pain setting. For example, after spinal surgery, co-administration of oral oxycodone to patients given PCA morphine resulted in better analgesia, lower morphine requirements (although total opioid use--oxycodone and morphine--in morphine equivalents was little different), less nausea and vomiting and earlier recovery of bowel function (114).

Prevention of withdrawal

A physical dependence on a drug, including an opioid, is "characterised by the emergence of a withdrawal (abstinence) syndrome if the drug is abruptly stopped, reduced in dose or antagonised" (84). Perioperative administration of the usual long-term opioid, or its equivalent, will usually prevent this.

Those taking other CNS depressants or CNS stimulants are also at risk of withdrawal from these drugs; however, symptoms may vary according to drug class. Withdrawal from alcohol and benzodiazepines in particular can cause life-threatening abstinence syndromes. If benzodiazepines are administered for the treatment of withdrawal signs and symptoms, especially when given concurrently with opioids, patient sedation levels must be monitored (74). Symptoms of withdrawal from CNS stimulant drugs are predominantly affective rather than physical (74) but withdrawal from methamphetamines can lead to sedation (115).

Key steps in the management of withdrawal are identification of risk (see 'Preoperative Management'), monitoring, drug replacement and symptom management. Clinicians should be able to recognise the withdrawal picture for each of the major drug classes (74). Withdrawal charts and protocols are used in many institutions but have limitations and cannot replace careful clinical assessment. Advice from a specialist drug and alcohol service may be needed (116). 'Anxiety' may be caused by drug withdrawal, a comorbid psychiatric diagnosis or by other factors and should be carefully evaluated.

Clonidine has long been used to manage opioid withdrawal symptoms (117). Although primarily an antihypertensive, when given in conjunction with opioids (in opioid-naive patients at least), it can also be opioid-sparing, though evidence is conflicting (74). Sedation and hypotension may also be more frequent (118).

Liaison with other clinicians, clinical services and healthcare workers

A collaborative, interdisciplinary approach, maintaining continuity of care and ensuring communication with usual care providers is crucial (72). Useful resources include: a pain clinic/pain medicine specialist, drug and alcohol service/ addiction medicine specialist, consultation-liaison psychiatrist, the patient's general practitioner, physiotherapy and social work. Referral to specialised services may need to be initiated, either as an inpatient or after discharge.

If problems are complex or the hospital admission prolonged, there is potential for dysfunctional interactions, such as fragmentation and conflict, either within the team or between the patient and members of the team (79,119). Strategies that may help minimise this include education of staff (120), clearly defined team member roles with one specialist/ service in charge of pain management decisions, good communication (including documentation), team meetings and providing the patient with a consistent message about management along with explicit behavioural limits (79). It is important that medical causes of disruptive behaviour, for example delirium from drug withdrawal, are excluded (79).

Specific issues in patients with an addiction

Addiction is characterised by a pattern of aberrant drug-taking behaviours and the compulsive use of a substance "despite the risk of physical, psychological or social harm to the user" (84). Patients with an opioid addiction may express concerns about inadequate pain relief, the possibility of withdrawal, and disrespectful treatment by staff due to stigmatisation (72). Specific strategies may be needed to deal with the sometimes difficult interactions that can occur (72,120). These include: ensuring a non-punitive, respectful approach to treatment in what may be challenging situations; recognising and acknowledging conditions that are painful; listening and responding to specific requests; recognising that 'difficult' behaviours may represent attempts to seek pain relief and providing reassurance that attempts are being made to provide good analgesia, while setting reasonable limits in terms of the medications that will be prescribed, including how much and how often (72).

Clinician concerns about possible 'drug-seeking' behaviour increase the complexity of acute pain management. It is probably preferable to err on the side of over-treating the occasional 'drug-seeker', rather than under-treating the patient in pain. Approaches include careful clinical judgement, assessing for legitimate causes of pain, challenging one's own stereotyping, communication with usual providers and jurisdictional authorities, drug security and use of rational prescribing policies and protocols promoting a standardised approach to management (121). On occasion, individuals with a history of addiction may use illicit drugs, for example those brought in by associates, while in hospital. Institutional guidelines about the management of such behaviour should be widely publicised (79).

Those in drug-free recovery or in addiction treatment programs may be concerned that their progress will be derailed by the acute pain episode and express a preference not to receive opioids in addition to their usual MMT or BMT (122). This requires reassurance, optimisation of non-opioid strategies, rational prescription of opioids and ongoing follow-up to support recovery maintenance. However, it is also important to explain that there is no evidence that the use of opioids to treat acute pain increases the rate of relapse and that a more likely trigger may be unrelieved pain (73).

Methadone maintenance therapy

MMT is usually given once a day. This is usually enough to suppress symptoms of opioid withdrawal for 24 hours but the duration of analgesia may be shorter (73,123). In those requiring treatment for acute pain, the usual daily methadone dose (or its equivalent if the patient is unable to take oral methadone) should be continued, with an alternative opioid given for additional analgesia. Sometimes, dividing the daily dose on a temporary basis, with or without an overall dose increase, may provide a background analgesic effect but additional opioid will usually still be required (74). If the methadone dose is increased, this should be done in consultation with the registered prescriber/addiction medicine specialist. Patients undertaking supervised reduction of their daily methadone dose in the community may be resistant to even a short-term dose increase for analgesia, as it may be viewed as a backward step in addiction recovery.

If enteral absorption is unreliable, methadone can be administered parenterally. Doses of half to two-thirds of the total daily oral dose can be given in three to four divided doses by intermittent intramuscular or subcutaneous injection or by continuous infusion (74,124). This is a specialised area of practice and consultation with those experienced in using parenteral methadone is advised. There is some evidence that sublingual methadone may be effective, safe and well tolerated (125).

Buprenorphine maintenance therapy

BMT is also usually given once a day, but in some patients the dose intervals may be extended further. Like methadone, the duration of analgesia may be shorter than the time over which opioid withdrawal is suppressed. Dividing the daily dose on a temporary basis (e.g. giving the buprenorphine in two to four equal doses throughout the day) may provide a background analgesic effect but again additional opioid will still be required (73,74).

Buprenorphine is often described as a partial muagonist and kappa-antagonist. Clinically however, it behaves as a full mu-opioid agonist for analgesia (126) and may have anti-hyperalgesic properties (126). It is also reported to have high opioid receptor affinity and slow offset kinetics, leading to concerns that the resultant blockade could interfere with effective acute pain management using other full mu-opioid agonists. As a result, conflicting recommendations exist (none based on high level evidence) as to whether high-dose buprenorphine (Subutex and Suboxone) should be continued or ceased in the perioperative period (73,127).

In a small series of five patients, good pain control after major surgery was achieved when usual sublingual buprenorphine doses (ranging from 2 to 24 mg/day) were continued and other full agonist opioids were given as needed (128). In an uncontrolled comparison of 22 BMT patients (daily buprenorphine dose 13.7 [+ or -] 6.6; range 4 to 32 mg) and 29 MMT patients (daily methadone dose 78.9 [+ or -] 49.0 mg; range 12.5 to 180 mg), first 24 hour postoperative PCA opioid requirements (in morphine equivalents) were 196 [+ or -] 128 mg and 180 [+ or -] 139 mg for BMT and MMT patients respectively. Pain scores (at rest and with movement) were similar (129). In both groups of patients, first 24 hour PCA requirements were higher, but again similar, when the maintenance drugs had been ceased perioperatively: BMT 245 [+ or -] 109 mg; methadone 281 [+ or -] 129 mg.

Therefore, continuation of usual BMT throughout the perioperative period is recommended with additional opioids given as required for management of acute pain.

Specific issues in patients with chronic pain

Chronic pain occurs in a psychosocial context and many factors may affect acute presentations (Table 1). Antidepressant, anti-anxiety and anti-neuropathic pain treatments should be continued where possible, although, this can be challenging in those who are unable to absorb oral medications (72). Many of these agents are not available in parenteral formulations.

Methadone has had a resurgence for use in the management of CNCP and cancer pain, particularly if there is a neuropathic component (130). In these settings it is commonly given as two to four doses per day and these should be continued or replaced perioperatively.

Transdermal buprenorphine patches are commonly prescribed for chronic pain (126) at doses far lower (480 [micro]g/day for a 20 [micro]g/hour delivery system) than those used in BMT (typically 4 to 32 mg/day). Except in circumstances of extreme haemodynamic compromise with poor peripheral perfusion, transdermal buprenorphine (and fentanyl) patches should be continued.

For those with cancer or non-cancer pain treated with ongoing continuous neuraxial (intrathecal or epidural) drugs, advice should be sought from the usual treating specialist (72). The neuraxial drugs can be treated as background requirements and the patient managed as for other opioid-tolerant individuals. Care should be taken if undertaking a neuraxial block or a surgical procedure close to the neuraxial drug delivery system.

Sleep disruption is common with chronic pain (131). Recommended management is a tricyclic antidepressant (amitriptyline or nortriptyline) in preference to benzodiazepines, which are associated with tolerance, addiction and disruption of sleep architecture. Tricyclic antidepressants have also demonstrated some OIH blocking effects in animal studies (132). Those taking benzodiazepines on a long-term basis should have these continued in hospital to avoid withdrawal symptoms. If in doubt, ensure drug withdrawal charts and protocols are used.

Other non-opioid strategies

During the past decade there has been increasing use of a wide range of adjuvant drugs in acute pain, aiming to improve quality of analgesia and reduce opioid requirements and opioid-related side-effects (74). Potential advantages of adjuvant drugs in opioid-tolerant patients include possible anti-hyperalgesic and anti-tolerance effects as well as lack of addictive potential or physical dependence. However, evidence of benefit, if any, has been reported only in opioidnaive patients.

Gabanoids are gaining popularity for use in acute pain, although evidence of benefit is conflicting. Meta-analyses have shown that use of perioperative gabapentin improved analgesia and reduced postoperative opioid consumption but increased the incidence of sedation (133,134). Perioperative pregabalin resulted in a significant, but small reduction in opioid requirements and a lower incidence of opioid-related side-effects, but no improvement in pain relief (135). The role of gabanoids in opioid-tolerant patients with acute pain has not been studied.

Examples of other adjuvant drugs for which there is some evidence of benefit in the opioid-naive, and for which more investigation in the opioid-tolerant patient may be warranted, include lignocaine (136,137), dexmedetomidine (138) and duloxetine (139).

DISCHARGE PLANNING AND MANAGEMENT

The main aims of management in opioid-tolerant patients are to treat acute pain as effectively as possible and facilitate return to the community and usual treating clinicians. There is no 'one size fits all' approach to management in this growing and heterogeneous group. The desire to minimise suffering and maximise rehabilitation opportunities must be tempered by the growing awareness, noted earlier, of prescription opioid abuse and diversion. The potential contribution of discharge opioid prescriptions to this community-wide problem necessitates a mindful approach to discharge planning.

Important considerations include the projected time to resolution of the acute episode, choice of analgesic agents and treatment duration, potential risks of opioid prescription and their management, varying legislative requirements in relation to opioid prescribing, communication with the patient's other treating practitioners (verbal and written as required) and follow-up arrangements, along with patient education and support. These issues should be considered and discussed with the patient and the treating team at an early stage in the admission so that unrealistic expectations are minimised. Usually the goal will be maintenance or resumption of usual medications as soon as possible, with any changes being for the short-term only.

For those with chronic pain, the underlying pain may not have changed. In most cases, the discharge plan will be to minimise alterations to preadmission medications prescribed for that pain. Exceptions to this may include situations where the admission opioids do not conform to acceptable guidelines (16) (e.g. where there may be inappropriate use of parenteral or very high doses of oral opioids). This may warrant consultation with or referral to a specialist service, either as an inpatient or an outpatient.

Similar considerations apply to those with a drug addiction, including those in an opioid substitution program with an authorised prescriber. Individuals outside such programs may prove more challenging to manage.

Prescription of additional opioids at time of discharge

In hospital, there are usually few limitations placed on the prescribing of opioids to patients who have an authorised prescriber (see footnotes, page 819) or an addiction to opioids (or other controlled drugs) other than a possible requirement to inform that prescriber. However, jurisdictional legislation may limit opioid prescribing in the community. Prescribers need to be aware of the relevant legislation in their country, state or territory. Links to information relevant to each Australian jurisdiction can be found on the Therapeutics Goods Administration website (140).

Formal authorisation may be required for opioid prescription for periods of longer than two or three months (141-144). Changes to the usual prescription, if considered necessary, may be possible if done in consultation with and with the agreement of the authorised prescriber. Prescription of opioids to those believed to be 'dependent' (see footnotes, page 819) on any controlled drug is commonly prohibited. Unlike most other Australian states, South Australian legislation allows patients on long-term opioid therapy, or with an addiction to a controlled drug, to be provided with opioids on discharge (that is, in addition to any authorised opioid and dose) for up to 14 days, as long as the authorised prescriber has been notified (145).

Even if there are no legislative restrictions on discharge opioid prescriptions, it would seem prudent to limit the planned duration of treatment with additional opioids in most opioid-tolerant patients, as for anyone prescribed opioids for acute pain management. Tighter restrictions may be appropriate for those with a drug addiction. When prescription of opioids (for self-medication) to known addicts is not permissible, it may be possible to arrange (through the authorised prescriber) daily or second-daily pick up of a limited and progressively decreasing amount of opioid, along with the usual MMT or BMT (75). Pain clinics can sometimes arrange similar administration schedules.

Potential risks of additional opioids

In many opioid-tolerant patients, prescription of opioids in limited doses for a limited period presents little risk. As in other acute pain settings, opioids may provide effective analgesia for early rehabilitation after surgery. However, care may be required in those for whom there is an increased risk of misuse or diversion. In the USA over half of the nonmedical users of prescription drugs reportedly sourced the drugs from friends or relatives who, in turn, often obtained them from just one doctor rather than a drug dealer or other stranger (146). In Australia in 2009 the most common sources of illicit morphine and oxycodone were a 'friend' (43 and 54% respectively) or known dealer (23 and 24%) (31).

While it is reasonable to take the potential for abuse and/or diversion into account, predicting those who might be 'at risk'--of either diversion or (usually unintentional) harm, or where there is a risk to or from family and friends--is difficult. The ability of clinicians to predict those who misuse or abuse opioids is poor (147). While estimated rates vary widely, the risk is said to be low in those with CNCP who have no current or past history of addiction or alcohol abuse (14). A number of tools are available to screen for potential opioid addiction or aberrant drug-taking behaviour (15,20,148,149). Based on this risk assessment, the decision can be made as to whether limited duration opioid prescription is appropriate or not.

Choice of analgesic agents

Opioids

If prescribing opioids on discharge (in addition to the patient's usual opioid and/or dose), consideration should be given to both the opioid type and duration of therapy. There is no evidence for 'best choice' or 'best' formulation (immediate or slow release). As acute pain is likely to vary with activity (which should be encouraged), it may be reasonable to use an 'activity-based' immediate-release opioid regimen. In other cases it may be appropriate, after discussion with the authorised prescriber, to temporarily increase the dose of the usual long-term opioid. Whatever choice is made, the duration of treatment should be limited and progressive weaning from the additional opioid is advisable, for example over seven days with continuation of opioid use after this time subject to review.

In some patients, choice of opioid will be determined by abuse liability (the 'attractiveness' of a substance for abuse). This depends upon factors such as availability, cost, peer preferences and features of the drug such as speed of onset, ability to use via different routes, psychotomimetic properties and potential to produce withdrawal syndromes (150,151). In a survey of nearly 500 recreational opioid users in the USA, the opioids rated most highly for attractiveness were immediate-release hydromorphone followed by SR oxycodone, transdermal fentanyl patches and SR morphine preparations (150). Some abuse-deterrent formulations of drugs have been developed (e.g. Suboxone, Targin[R], Mundipharma Pty Limited, Sydney, NSW [oxycodone and naloxone] and Talwin NX[R], Sanofi-Aventis U.S., Bridgewater, New Jersey, USA [pentazocine and naloxone]). In future, it is likely that more will become available (152).

[FIGURE 2 OMITTED]

Tramadol prescription does not have the same regulatory limits, including for those with an addiction. It has a lower abuse potential. However, it should again only be used for the short-term treatment of acute pain and not with the aim of changing an individual's usual chronic pain therapy unless discussed with the usual prescriber.

Non-opioid analgesics

Paracetamol or NSAIDs that have been started in hospital can be continued after discharge, although limiting the total duration of NSAID use may be appropriate.

Combination 'over-the-counter' analgesics

Some patients may choose to use or increase their use of combination 'over-the-counter' medications--usually combinations of low-dose opioid and either paracetamol or an NSAID. In addition to being more expensive than the component drugs, there is little if any evidence of benefit for most combination analgesic preparations compared with the individual drugs alone (153). Serious morbidity has resulted from misuse of over the counter codeine-ibuprofen combinations (154). In the absence of supporting evidence of benefit, use of such combination analgesics is discouraged.

Duration of treatment

As the primary aim will be appropriately time-limited treatment of the acute episode after inpatient care, the discharge plan should ideally include suggestions for estimated duration of therapy and a dose reduction schedule. It is important to discuss a plan for dose reductions of any analgesics with the patient and helpful to provide the patient and his or her community medical practitioner with a written dose reduction schedule.

The World Health Organization 'Pain Ladder' was developed to guide management of cancer pain (155) with analgesic drugs to be given in ascending order (a 'step-up' approach) until the patient is comfortable: non-opioids (aspirin and paracetamol), then mild opioids (codeine) and finally strong opioids. A simple concept for patients and other staff to understand is the 'Reverse Pain Ladder' or 'step-down' approach (Figure 2) in which the same steps are used but in reverse order--at least until baseline opioid use is re-established.

Involvement of other health professionals

Discharge planning should include communication (both verbal and written as required) with the usual treating doctors. Referral to specialised services such as a pain clinic or addiction specialist may need to be initiated.

CONCLUSIONS

The number of opioid-tolerant patients requiring treatment for acute pain is increasing and effective management of that pain can be challenging. However, involvement of the patient and all treating clinicians in developing management plans (summarised in Table 2) that start before admission where possible and continue into the post-discharge period, will promote safe and effective pain relief, along with continuity of long-term care.

ACKNOWLEDGEMENT

The authors gratefully acknowledge the assistance of Colin M. Brown, Acting Manager, Drugs of Dependence Unit, Drug and Alcohol Services South Australia, in reviewing this paper.

A. Somogyi was supported by NHMRC Project Grants 565387 and 1011521.

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FOOTNOTES

The term "authorised prescriber" is used in this review as a general term to indicate those medical practitioners who are either authorised to prescribe opioids to patients with chronic pain in the longterm or authorised to prescribe drugs used in the pharmacotherapy of opioid addiction. It may have other more specific meanings in some jurisdictions.

In legislative and regulatory terms, the word "dependence" usually has a more general meaning than "physical dependence" (defined earlier). It is often used to refer to an addiction to a controlled drug (i.e. "drug of dependence", also called "dangerous drug" in some jurisdictions).

C. A. HUXTABLE *, L. J. ROBERTS ([dagger]), A. A. SOMOGYI ([double dagger]), P. E. MACINTYRE ([section])

Department of Anaesthesia, Pain Medicine and Hyperbaric Medicine, Royal Adelaide Hospital and Discipline of Pharmacology, School of Medical Sciences and Discipline of Acute Care Medicine, University of Adelaide, Adelaide, South Australia and Department of Anaesthesia and Pain Management, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia

* M.B., B.S., F.R.A.C.G.P., F.A.N.Z.C.A., M.R.C.A., Consultant Anaesthetist, , Department of Anaesthesia, Pain Medicine and Hyperbaric Medicine, Royal Adelaide Hospital.

([dagger]) M.B., B.S. (Hons), B.Med.Sc. (Hons), F.A.N.Z.C.A., F.F.P.M.A.N.Z.C.A., Director, Acute Pain Service, Department of Anaesthesia and Pain Management, Sir Charles Gairdner Hospital.

([double dagger]) Ph.C., M.Sc., Ph.D., F.F.P.M.A.N.Z.C.A., Professor, Discipline of Pharmacology, School of Medical Sciences, University of Adelaide.

([section]) B.Med.Sc., M.B., B.S., M.H.A., F.A.N.Z.C.A., F.F.P.M.A.N.Z.C.A., Director, Acute Pain Service, Department of Anaesthesia, Pain Medicine and Hyperbaric Medicine, Royal Adelaide Hospital and Associate Professor, Discipline of Acute Care Medicine, University of Adelaide.

Address for correspondence: Dr C. Huxtable, Department of Anaesthesia, Pain Medicine and Hyperbaric Medicine, Royal Adelaide Hospital, Adelaide, SA 5000. Email: christine.huxtable@health.sa.gov.au

Accepted for publication on June 13, 2011.
TABLE 1
Pain-related assessment in opioid-tolerant patients

Information from all Additional Additional
opioid-tolerant information in information in
patients patients with CNCP patients with an
 or cancer pain addiction

Current treatment Pain diagnosis Opioid substitution
providers therapies and doses
 (methadone,
 buprenorphine)

Opioid and Usual pain scores Other prescribed or
non-opioid illicit substance
medications use (polyabuse is
 common)

Dose verification of Functional status Routes of
all relevant administration
medications

Non-prescribed drugs Prognosis (cancer Where relevant,
(e.g. pain) registered
over-the-counter and prescriber and
illicit drugs, dispensing pharmacy
alcohol, nicotine)

Drug allergies and Psychospiritual Medical and
reactions issues (including psychiatric co-
 end-of-life issues, morbidities (e.g.
 anxiety, depression, blood-borne viruses,
 coping style and hepatic disease,
 strategies) other infections,
 chronic pain,
 personality
 disorder)

Experiences and Where relevant, the
expectations of authorised
acute pain prescriber of any
management opioids

Support systems Presence of invasive
after discharge pain treatment (e.g.
 intrathecal pump,
 spinal cord
 stimulator)

 Medication misuse or
 addiction

 Expectations about
 their admission
 (e.g. expectation
 that chronic back
 pain will be
 improved after
 spinal surgery;
 palliative vs
 curative surgery in
 patients with
 cancer)

CNCP=chronic non-cancer pain.

TABLE 2
Principles of acute pain management in opioid-tolerant patients

Preoperatively

1. Preoperative Assessment (Table 1)
planning
 Patient education including management plan
 (admission to discharge)

 Ensure usual prescribed opioid (including
 buprenorphine) is taken on the day of surgery

 In MMT or BMT, consider arranging a 'take
 away' dose for self-administration on day of
 surgery

 Liaise with other healthcare professionals as
 indicated

Inpatient management

2. Intraoperative Replace usual opioid
analgesia
 Titrate additional opioid to effect

 Consider risk of awareness

 Use non-opioid and adjuvant drugs

3. Postoperative
analgesia

a. Give adequate Incremental doses that are higher than the
doses of opioid in age-based doses usually prescribed for opioid-
addition to usual naive patients may be needed (including higher
opioid PCA bolus dose)

 Much higher than expected total daily opioid
 doses may be required

 Titration to effect for each patient remains
 important

 Monitor pain, functional activity scores and
 sedation

 Expect the need for more frequent review and
 adjustment of dosing

b. Strategies that Opioid rotation
may help to
attenuate tolerance Ketamine
or OIH

c. Use of non- Limited or no evidence of benefit in opioid-
opioid and adjuvant tolerant patients but may be useful:
analgesic drugs
 Paracetamol and/or NSAIDs

 Gabanoids

 Lignocaine

d. Regional Central neuraxial or other regional blockade
analgesia (consider a catheter technique)

 Useful as part of a multimodal regimen

 Neuraxially administered opioids may not
 prevent opioid withdrawal

4. Prevention and Maintain usual opioid dose equivalent
treatment of
withdrawal syndromes Give usual opioid (including buprenorphine) or
 give equivalent dose of another opioid or same
 opioid by a different route

 Monitor for drug withdrawal (opioids and other
 drugs)

 Drug replacement or symptom management (e.g.
 clonidine, benzodiazepines)

5. Close liaison In-hospital and post-discharge pain management
with other treating
clinicians and Related social, psychiatric and behavioural
specialist teams issues

Management after Liaison with community providers
discharge

 Discharge management plans

 Consider legislative restrictions for opioid
 prescribing

 Consider early follow-up or relevant new
 referral

MMT=methadone maintenance therapy, BMT=buprenorphine maintenance
therapy, PCA=patient-controlled analgesia, OIH=opioid-induced
hyperalgesia, NSAID=nonsteroidal anti-inflammatory drugs.
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Publication:Anaesthesia and Intensive Care
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Date:Sep 1, 2011
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