Opioid-induced hyperalgesia—Pathophysiology and clinical relevance

Acute Pain (2007) 9, 21—34

REVIEW

Opioid-induced hyperalgesia—–Pathophysiology and clinical relevance Wolfgang Koppert ∗ Klinik f¨ ur An¨ asthesiologie, Universit¨ atsklinikum Erlangen, Krankenhausstrasse 12, D-91054 Erlangen, Germany Received 6 April 2006 ; received in revised form 27 October 2006; accepted 9 November 2006 Available online 8 January 2007 KEYWORDS Opioids; Hyperalgesia; Tolerance; NMDA-receptors; Postoperative pain

Summary Opioids are the drugs of choice for the treatment of moderate to severe acute and chronic pain. However, clinical evidence suggests that — besides their well-known analgesic activity — opioids can increase rather than decrease sensitivity to noxious stimuli. Based on the observation that opioids can activate pain inhibitory and pain facilitatory systems, this pain hypersensitivity has been attributed to a relative predominance of pronociceptive mechanisms. Acute receptor desensitisation via uncoupling of the receptor from G-proteins, up-regulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA)-receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioidinduced hyperalgesia is observed both in animal and human experimental models. Brief exposures to ␮-receptor agonists induce long-lasting hyperalgesic effects for days in rodents, and also in humans large-doses of intraoperative ␮-receptor agonists were found to increase postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients is often associated with a requirement for increasing doses and the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, ␣2 -agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor selectivity. © 2006 Elsevier B.V. All rights reserved.

Contents 1. 2.

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Introduction................................................................................................ Antinociceptive systems.................................................................................... 2.1. Modulation of membrane potential ..................................................................

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1366-0071/$ — see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.acpain.2006.11.001

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W. Koppert 2.2. Deactivation of adenylate cyclase ................................................................... 2.3. Receptor trafficking ................................................................................. 2.4. Descending inhibition................................................................................ Pronociceptive systems .................................................................................... 3.1. Receptor-desensitisation ............................................................................ 3.2. Activation of adenylate cyclase...................................................................... 3.3. NMDA-receptor activation ........................................................................... 3.4. Release of peptides with opioid-antagonistic properties (anti-opioids)............................... 3.5. Descending facilitation .............................................................................. Experimental investigation of opioid-induced hyperalgesia ................................................. 4.1. Fentanyl............................................................................................. 4.2. Alfentanil............................................................................................ 4.3. Remifentanil......................................................................................... 4.4. Morphine ............................................................................................ 4.5. Methadone .......................................................................................... 4.6. Heroin............................................................................................... Therapeutic implications................................................................................... 5.1. NMDA-receptor antagonists .......................................................................... 5.2. ␣2 -Agonists .......................................................................................... 5.3. COX-inhibitors and paracetamol ..................................................................... 5.4. Opioid rotation ...................................................................................... Conclusion ................................................................................................. References .................................................................................................

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1. Introduction Tissue damage during surgery elicits an activation of nociceptive systems. High threshold mechano-, thermo- and chemo-sensors, the nociceptors (lat.: nocere = to damage), rapidly transmit information about the degree and site of damage to the central nervous system. Depending on the type and extent of damage, sensitisation processes leading to increased pain sensitivity, i.e. hyperalgesia, can be observed in the peripheral and central nervous systems (Fig. 1A). Peripheral sensitisation can be observed particularly during inflammation and other pathological tissue changes. They can sensitise nociceptors locally by lowering their activation thresholds or de novo sensitise primarily insensitive, so-called ‘silent’ nociceptors [1—6]. Central sensitisation is characterised by the increased spontaneous activity, and expansion of receptive fields of dorsal horn neurons [7—10]. One crucial event of this process is the activation of spinal N-methyl-Daspartate (NMDA-) receptors by glutamate [11—13]. Central sensitisation processes can, thus, not only initiate but also maintain pain conditions that long out-last the triggering event. Furthermore, sensitisation processes also appear, independent of pain perception during anesthesia and are often the basis for the development of postoperative pain. Several publications show that perioperative antinociceptive therapy with opioids can reduce postoperative pain [14—20]. Furthermore, opioids are the drugs of choice in tumor pain therapy,

Fig. 1 (A) Hyperalgesia is characterised by a leftward shift of the stimulus—pain curve, i.e. a normally non-painful stimulus becomes subsequently noxious (=Allodynia), while a normally painful stimulus increases in intensity. (B) A rightward shift of the dose—effect curve can be observed for the tolerance development i.e. the drug loses its potency.

Opioid-induced hyperalgesia for the treatment of strong trauma pain, and for concomitant medication in patients with longterm artificial respiration. Thus, it is remarkable that patients with similar pain conditions often require very different quantities of opioids. Factors that influence this variability include pain type (nociceptive-, inflammatory- or neuropathic-pain), psychosocial condition, and genetic disposition (gender or ethnicity) [21,22]. Habituation to opioids or use of concomitant medication can also cause variation in opioid requirement. The concept of ‘habituation’ is based on a multitude of adaptive responses of the organism to exogenous opioids. In this discussion, we include these adaptive responses in the term tolerance development [23]. The (analgesic) tolerance is characterised by decreasing analgesic effect during long-term application of opioids, necessitating dose increases (Fig. 1B). Tolerance development is not based on intensified pain sensation, but can be observed even without overt pain experience [24]. However, not only decreasing analgesic effects are observed clinically following administration of opioids, but pain may also increase above the preexisting level or hyperalgesia may occur [25—29]. This would imply that the decreasing analgesic effect is based not only on a reduced antinociceptive potency of the opioids, but additionally on the activation of opposing, i.e. pronociceptive systems [30—33]. The basic idea of such compensatory reactions to drug application has been described in the ‘‘Opponent Process Theory’’ [34]. In this theory the interplay between a drug-induced central effect and the induced counteracting endogenous response is discussed. The drug-induced effects (such as opioid-induced analgesia) have a short onset and are stable upon repetition, whereas the counteracting process (such as opioid-induced hyperalgesia) has a delayed onset, which increased upon repetition (Fig. 2). According to this theory the observed effect of opioids would be determined by the interaction of the two opposing anti- and pro-nociceptive processes [33]. The molecular mechanisms underlying these anti- and pro-nociceptive mechanisms will be discussed below. Additionally, the relevance of these mechanisms to human and animal experimental investigation will be described and approaches to therapeutic modulation of opioid-induced hyperalgesia will be introduced.

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Fig. 2 The ‘Opponent Process Theory’ demonstrates the function of an activated, positive process (a-Process) simultaneously with a compensatory (opposing) response, i.e. a negative process (b-Process). The opioid-induced analgesia and hyperalgesia are due to the interaction of the two opposing processes (a + b). A repeated exposure to opioids results in a decrease of analgesic effect via the increasing activation of pronociceptive systems (A), while a fairly long-term opioid therapy reduces the analgesic effect (B). Based on [33,34].

opioid receptors have been identified (␮, ␦, ␬, ORL1). In addition, eight isoforms (␮1—3 , ␦1—2 , ␬1—3 ) and numerous subtypes have been pharmacologically characterised. The opioid receptors mediate their effects via an activation of guanine-nucleotidebinding protein (G-proteins), particularly — but not exclusively —pertussis toxin-sensitive Gi/o -protein [35].

2.1. Modulation of membrane potential

2. Antinociceptive systems Opioids activate peripheral, spinal, and supraspinal opioid receptors. To date, four different groups of

The ␤/␥-subunit of G-proteins leads to a K+ -efflux (KIR ) and to the closing of voltage-gated Ca2+ channels [36] leading to hyperpolarisation and reduced neuronal excitability. Possible mechanisms

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Fig. 3 Schematic diagram of antinociceptive and pronociceptive mechanisms mediated by ␮-agonists. For further information, see text.

of antinociceptive opioid effects are summarised in Fig. 3.

2.2. Deactivation of adenylate cyclase A Gi/o -protein mediated activation of opioid receptors inhibits adenylate cyclase and, consequently, causes a decrease of intracellular cyclic adenosine monophosphate (cAMP), which can also lead to hyperpolarisation and inhibition of neurotransmitter release such as glutamate and substance P (SP) at peripheral, spinal and supraspinal levels [37—39].

2.3. Receptor trafficking After activation, the opioid receptor becomes phosphoralised by G-protein-regulated receptor kinases (GRK) and is thereby separated from the G-protein. As a result, the receptor increases its affinity for the cellular protein arrestin and the subsequently activated receptor—arrestin complex can initiate endocytosis [40]. Following internalisation, the receptor is either ‘recycled’ and will reexpress at the cell surface or it will be degraded. Via internalisation and re-expression of receptors, the opioid-receptor bond becomes intermittently detached and initiates other adaptive intracellular processes that result in tolerance development [41,42]. This theory explains observations that the ␮-agonist Morphine does not possess a significant capacity for receptor internalization but exhibits a high potential for tolerance development [43,44].

2.4. Descending inhibition Descending inhibition originates in the periaqueductal gray matter of the midbrain (PAG) and the rostral ventromedial medulla oblongata (RVM). In the RVM, three classes of neurons can be discerned: Off-cells are inhibited by painful stimuli, On-cells increase their firing rate upon painful stimulation, and neutral cells do not respond to painful stimuli [45—47]. Off- and On-cells project onto dorsal horn neurons to inhibit and facilitate, respectively, the synaptic transmission of nociceptive inputs [46,48]. The central analgesic effect of ␮-agonists is attributed to an inhibition of On-cells and an activation of Off-cells [49,50]. In addition to direct opioid receptor effects, affinity to or interaction with other antinociceptive systems such as GABAergic and glycinergic neurons [51—53] are important factors to determine an opioid’s antinociceptive potency.

3. Pronociceptive systems Long before Pert and Snyder (1974) first described opioid receptors, it was known that long-term opioid therapy could cause a renewed increase of initially suppressed pain, which was initially attributed to a loss of the antinociceptive capacity of opioids. In recent years a new hypothesis was brought up that proposed activation of pronociceptive systems by opioids [30,31,33]. Possible mechanisms of pronociceptive opioid effects are summarised in Fig. 3.

Opioid-induced hyperalgesia

3.1. Receptor-desensitisation Opioid receptors show a rapid-onset desensitisation, despite continuous availability of ligands. This process can be attributed primarily to protein kinase C (PKC)-mediated phosphorylation and internalisation of opioid receptors. Currently, at least a dozen PKC-isoforms have been described, of which PKC␥ has the greatest impact on the regulation of spinal nociceptive processes [54,55]. The activation of PKC causes phosphorylation in many receptors and ion channels including ␮-opioid receptors and NMDA-receptors [56,57], but opioid receptor phosphorylation can also be mediated by ␤-adrenergic receptor kinase 2 and ␤-arrestin 2 [58,59]. The desensitisation represents a homologous process, i.e. ␮-opioid receptors can desensitise only if ␮selective agonists are applied [43]. Currently, a desensitisation can be demonstrated for nearly all opioids in clinical use [44,60,61]. Important in this context is the fact that opioid receptors often exist as dimers or oligomers. Thus, homodimers (␮/␮, ␦/␦, ␬/␬) and heterodimers (␮/␦, ␦/␬, ␦/␤2 , . . .) can also be observed [62,63]. Dimers and oligomers are, thus far, the only explanation for the existence of the numerous, pharmacologically defined opioid receptor subtypes without a relevant gene. Furthermore, the fact that the application of a low concentration of ␦-selective agonists prevents the desensitisation against the ␮-agonist morphine substantiates evidence of the di- and oligo-merisation of ␮- and ␦-opioid receptors, respectively [41].

3.2. Activation of adenylate cyclase As discussed above opioid receptor coupled Gi/o activation reduce cAMP levels. However, long-term application of ␮-agonists can cause Gs -protein mediated up-regulation of adenylate cyclase activity resulting in increased cAMP levels [64—66]. Increased cAMP level may via presynaptic activation, increase the release of excitatory neurotransmitters at a spinal level [67,68], and lead to a GABA-mediated increased transmission in the PAG and in other areas of the midbrain [51,69,70]. These findings are supported by observations that benzodiazepine, depending on spinal or supraspinal application, can increase or attenuate the analgesic effect of opioids [71—75].

3.3. NMDA-receptor activation The activation of PKC causes a phosphorylation of NMDA-receptors with a neutralisation of Mg2+ -blocks and increased Ca2+ -influx. The spinal NMDA-receptor system is a functionally important

25 pronociceptive system which can become activated via opioids. Of particular significance is that opioids can develop synergistic effects with excitatory amino acids, i.e. the neurotransmitters, which play a crucial role in the initiation and maintenance of central sensitisation [76]. The activation of NMDAreceptors causes a Ca2+ -influx, contributing, via a further increase of PKC activity, to the phosphorylation and inactivation of opioid receptors. In addition, an activation of neuronal NO-synthase induces the generation of NO (nitric oxide). It can be demonstrated that the induction of the supraspinal isoform of NO synthesis (nNOS1 ) reduces the antinociceptive potency of ␮-agonists and that the non-selective inhibitors of NOS counteract tolerance development [77—80].

3.4. Release of peptides with opioid-antagonistic properties (anti-opioids) Long-term application of opioids can induce peptides with pronociceptive properties. Currently, the most important peptides are cholecystokinin (CCK), neuropeptide FF (NPFF) and nociceptin (orphanin FQ). Dynorphin A might play an important role in this process. Primarily due to its ␬-agonistic properties, it is classified as an endogenous opioid [81]. Recent studies have shown that Dynorphin A possesses relevant pronociceptive properties, which result, in part, in the activation of the NMDAreceptor system [82—84]. All mentioned peptides exhibit increased spinal expression with the application of opioids [85—93]. Furthermore, blocking of their specific receptors was shown to potentate the opioid effect [94—98].

3.5. Descending facilitation In contrast to descending inhibition, a facilitation of synaptic transmission in dorsal horn neurons can be observed with continuous application of ␮-agonists [96,99,100]. It is presumed that long-term application of opioids, via pronociceptive intracellular systems, also causes a reversal of activation patterns of On-cells in the RVM and, thus, results in the development of hyperalgesia [96]. CCK and nociceptin also facilitate these pronociceptive effects, while they inhibit ␮-agonist induced activation of Off-cells [101,102]. ␬-agonists can, in contrast, weaken ␮-agonist induced facilitation, while interfering presynaptically with activated glutamatergic synapses [103]. Dourish et al. investigated morphine analgesia as well as opiate tolerance and dependence in rats after application of the selective CCK-B antagonist L-365,260 and found

26 enhanced analgesia induced by morphine [104]. Accordingly, intrathecal application of CCK-8 or CCK-receptor agonists were also shown to interfere with morphine tolerance [105], while CCK-receptor antagonists potentate the analgesic effects of morphine and endorphin and prevent the development of morphine tolerance [91,97,98,106]. These data suggest that CCK itself can attenuate morphineinduced analgesia in rodents via CCK-B receptors. Other pronociceptive properties depend on pharmacokinetic characteristics of individual opioids. Of clinical importance are the morphine metabolites Morphine-3-Glucuronid (M-3-G), and Morphin6-Glucuronid (M-6-G). M-6-G has potent analgesic effects [107], whereas M-3-G exhibits partial ␮antagonistic and excitatory properties [108—110]. During long-term application of morphine, M-3-G can accumulate, cross the blood—brain-barrier and inhibits morphine and M-6-G.

W. Koppert morphine application [113—115]. In line with these results, patients receiving high intraoperative fentanyl doses (15 ␮g/kg), as opposed to low fentanyl doses (1 ␮g/kg), have significantly higher postoperative morphine consumption [116].

4.2. Alfentanil In animal experiments, a reduction of analgesic effect can already be observed during the first hour after alfentanil application [117,118]. In addition to PKC-mediated coupling of G-proteins, activation of NMDA-receptor systems can underlie this effect [117,119]. The clinical relevance of these findings is, however, questionable. In postoperative pain therapy, no significant dose increase of alfentanil has been found for a 6-h infusion [120] indicating the absence of relevant tolerance development.

4.3. Remifentanil

4. Experimental investigation of opioid-induced hyperalgesia Opioid-induced hyperalgesia has been investigated studying pain behaviour in animal models and using psychophysics in humans. Below, we focus on the effects of 4-anilinopiperidine opioids used today in the perioperative setting (fentanyl, alfentanil and remifentanil) and the opioids used in pain and substitution therapy (morphine, methadone and heroin) will be characterised based on animal and human experimental research.

4.1. Fentanyl In animal experiments, after repeated application of fentanyl, a dose-dependent reduction of pain thresholds can be observed after fading of the analgesic effect [111]. With application of 80 ␮g/kg, this effect lasts only 1 day, while an application of 400 ␮g/kg produces a heightened pain sensitivity that can still be observed after 5 days. Similarly, the painfulness of an experimentally produced inflammation is further increased after cessation of fentanyl therapy [112]. Since this hyperalgesia can be alleviated, in all cases, by the NMDA-receptor antagonist ketamine, fentanyl is supposed to already have caused a significant activation of NMDA-receptor systems after shortterm application. [111,112]. This could also explain the partial loss of analgesic effect of morphine when applied immediately after the fading fentanyl analgesia [113,114]. It has also been demonstrated that the combination of fentanyl with ketamine or N2 O restores the analgesic strength following

Similar observations have been made with the fastacting opioid remifentanil. One study reports that continuous infusion of remifentanil in healthy volunteers leads to a rapid decrease of its analgesic effect to a quarter of its maximal effect [121]. The lack of a control group as well as the exclusion of many volunteers, however, confounds these results. In other studies, a clear dose-dependent effect has been demonstrated for remifentanil; also, during a 3-h infusion, no loss of effect of the opioid was observed. [122,123]. These findings were verified by clinical observations in postoperative pain therapy [120,124,125]. Nevertheless, there is evidence that remifentanil, even after a short period, causes a clinically relevant activation of pronociceptive systems leading to increased pain responsiveness after the discontinuation of the opioid. Patients who underwent abdominal surgery, and received high intraoperative remifentanil dose (0.3 ␮g/kg/min) had a significantly higher postoperative morphine consumption than the patient groups that received a low intraoperative dose (0.1 ␮g/kg/min) of remifentanil [28]. However, if remifentanil is administered for a shorter period and at a lower dose, no clinically significant difference can be observed in postoperative pain medication [126]. These results imply that the activation of pronociceptive systems is time and dose related. Experimental investigations support these ideas. In several studies with healthy volunteers, a dose-dependent increase in pain sensation and a threshold decline for mechanical stimuli have both been observed after the discontinuation of opioids [127—129] (Fig. 4). The combination of remifentanil with ketamine also causes an inhibition of

Opioid-induced hyperalgesia

Fig. 4 (A) Time course of pain ratings during continuous electric stimulation in humans. The current was delivered by a stainless-steel needle which was inserted intradermally over a length of 1 cm at the central volar forearm of the subjects. A skin surface electrode (1.0 cm × 0.5 cm) was attached directly above the needle serving as anode. The infusion of remifentanil causes an initial, dosedependent decrease in pain intensity. After completion of the infusion, a significant pain increase can be observed. (B) During the infusion of remifentanil, the observed antihyperalgesic effects are associated with a significant increase in the area of secondary mechanical hyperalgesia after completion of infusion. Shown are averages and standard error (n = 13). Based on [129].

central sensitisation processes. [127,130]. These results are in line with clinical observation according to which intraoperative application of ketamine (Bolus 0.15 mg/kg, followed by a long-term infusion of 2 ␮g/kg min) in addition to remifentanil, caused a significant reduction of postoperative morphine consumption [131]. In a human volunteer model using electrically evoked pain remifentanil increases this electrically evoked pain sensation upon cessation. This increase of pain has been attributed to remifentanil induced opioid receptor internalisation and consecutively reduced analgesia by endogenous opioids, similar to an acute withdrawal [129]. The additional application of ␣2 -agonist clonidine inhibits development of the acute withdrawal [130], whereas ketamine did not [130,132]. Thus, remifentanil-induced hyperalgesia seems to involve different ketamine-sensitive and -insensitive pronociceptive systems.

4.4. Morphine In contrast to the observations in the perioperative setting, hyperalgesic pain conditions already emerge during administration in a longterm (days to weeks) application of this opioid [25,26,133,134]. It can be shown experimentally that both, systemic and intrathecal applications of morphine activate the NMDA-receptor system. Specific (MK-801) and unspecific NMDA-

27 receptor antagonists (ketamine, dextromethorphan) cause a significant reduction of hyperalgesia [30,57,133,135—139]. These findings are supported by clinical observations, in which a combination of morphine with ketamine or dextromethorphan reduces analgesic consumption and prevents the occurrence of paradoxical pain, particularly in chronic use [140—142]. Additionally, dose-dependent excitatory effects can be observed under morphine therapy and are usually attributed to accumulation of M-3-G in plasma [143—145]. In addition to pain increase and the occurrence of new pain qualities, myoclonia and seizures can indicate an accumulation of M-3-G [143,145]. The rotation to another opioid leads to an immediate improvement in physiological condition [146].

4.5. Methadone Unlike morphine, methadone functions antagonistically with the NMDA-receptor [147,148]. It can be shown that this antinociceptive interaction contributes to an improvement of analgesia [149]. Although a cross-tolerance with morphine is assumed [150,151], the tolerance development and resulting hyperalgesia under morphine can be prevented by methadone [150,152]. In addition to the blocking of NMDA-receptors, higher receptor specificity of methadone is also crucial for these effects [53,153]. However, a decrease of pain thresholds can also be observed under therapy with methadone [27,154]. These findings can be traced, in part, back to the study design and the pharmacokinetic properties of the opioid: methadone possesses a very long half-life and, therefore, was administered only once per day. Thus, the findings might indicate a brief withdrawal with clinically relevant activations of pronociceptive systems [155].

4.6. Heroin Comparatively, heroin appears to exhibit much stronger and distinct hyperalgesic effects. In experimental investigation, a dose-dependent decrease of mechanical (pain) thresholds, lasting several days, can already be observed after a single application [156,157]. After a several day application, a significant activation of pronociceptive systems is still apparent after 4 weeks [158,159]. In all cases, this sensitisation process can be alleviated or inhibited via pretreatment with NMDA-antagonists. In summary, it can be concluded that, in current clinical practice, the development of opioid-induced hyperalgesia must be considered if

28 hyperalgesic pain conditions occur during long-term therapy with opioids. It seems to be clear that the sensitisation process is already induced after shortterm use and, thus, may mask part of the analgesic effect even many days after discontinuation.

5. Therapeutic implications In many cases, an increased demand for opioids can be attributed to increasing input of nociceptive afferents or, particularly in chronic and tumor pain therapy, a situational variation of pain experiences (fear, grief and isolation) [23], but not to an opioid-induced hyperalgesia. However, in these clinical conditions increased pain can be mediated by activation of the same pronociceptive systems (NMDA-receptor system, descending facilitation) and thus, therapeutically may have the same implications.

5.1. NMDA-receptor antagonists The combination of opioids with the NMDA-receptor antagonists ketamine or dextromethorphan is closely investigated in the perioperative setting. Anti-hyperalgesic effects of ketamine on the development of postoperative pain were also observed in a low-dose regimen [160] consisting of an initial intravenous application of 0.5—1 mg/kg followed by a continuous infusion of 10—20 ␮g/kg min. With application of S-ketamine, this dosage should be reduced by 50%. Dextromethorphan, the D-isomer of codeine-derivative levorphanol, is similarly effective. The preoperative application of 1—5 mg/kg dextromethorphan significantly reduces postoperative morphine consumption [161—163]. Also, in chronic pain, the dose increases of morphine can be prevented by the combination of morphine with dextromethorphan at a ration of 1:1 [141].

5.2. ␣2 -Agonists The perioperative application of 1—2 ␮g/kg clonidine significantly increases the analgesic opioid effects in postoperative pain therapy [164—167]. It can be shown that clonidine not only strengthens the opioid effect, but also counteracts the tolerance development [167,168]. Furthermore, the development of withdrawal symptoms after discontinuation of an opioid is effectively inhibited by clonidine [130,169]. Recent results suggest that ␣1 -agonists can also be effective in this process [170].

W. Koppert

5.3. COX-inhibitors and paracetamol Cyclooxygenase (COX)-inhibitors and paracetamol also exhibit preventive effects on the development of postoperative pain and increased demand for opioids [171—174]. COX-inhibitors reduce the spinal release of excitatory neurotransmitters and act synergistically with NMDA-receptor antagonists [175,176]. In addition to metamizole two new drugs, paracetamol and parecoxib, were recently made available in Europe for authorised intravenous administration. Both compounds are characterised by a lack of effect on blood clotting and on the gastrointestinal tract and, thus, are also highly adequate for use in the perioperative setting. Recently, it has been shown that preventive administration of parecoxib led to an amplification of remifentanil-induced antinociceptive effects during the infusion and diminished significantly the hyperalgesic response after withdrawal [177]. In contrast, parallel administration of parecoxib did not show any modulatory effects on remifentanilinduced hyperalgesia. These new results confirm clinically relevant interaction of ␮-opioids and prostaglandins in humans, and the particular importance of an adequate timing for the antihyperalgesic effect of COX-2 inhibitors in this setting. However, it is yet unclear as to whether other COX-inhibitors and paracetamol show similar properties.

5.4. Opioid rotation The majority of clinically used opioids are characterised by intrinsic activity at the ␮-receptor. However, as compared to ␬-agonists, ␮-agonists exhibit clear, pronounced pronociceptive properties [44,103]. It can be shown that both the synthetic ␬-agonist U-50,488H and also the combined ␬-agonist/␮-antagonist nalbuphine can delay or inhibit a morphine tolerance [178—180]. Interestingly, early studies with transdermal application of buprenorphine, a partial ␮-agonist/␬-antagonist, show similar results. After the rotation of buprenorphine, a sustained reduction of opioid consumption can be observed in many patients [181]. Furthermore, buprenorphine was found to exert lasting antihyperalgesic effects in an experimental pain model [182]. These antihyperalgesic effects showed a significantly longer half time as compared to its analgesic effects and contrasts the delayed increase of hyperalgesia observed following administration of pure ␮-receptor agonists. It is yet unclear as to whether these effects of buprenorphine also translate into improved treatment of pain states dominated by central sensitisation.

Opioid-induced hyperalgesia However, opioids with solely ␮-agonistic properties are recommended for opioid rotation, too. The rationale of this opioid rotation is based on incomplete and the clinically often very difficult to predict cross-tolerance between the ␮-agonists. Morphine is, therefore, often rotated with transdermal fentanyl, hydromorphone, oxycodone or methadone [183—185]. An improvement of analgesic quality and a reduction of undesirable side-effects can be achieved in two out of three patients. Methadone in particular seems to exhibit advantages due to its greater affinity to the ␮receptor, as well as an antagonistic effect at the NMDA-receptor [183,186,187]. The recommended dosage after opioid rotation is 50% of the calculated equivalent dose and, if necessary, a brief high titration, since the individual strength of equivalent doses can vary due to the activation of pronociceptive systems [23]. However, there is not yet clinical evidence for one opioid being more effective in opioid rotation than another one.

6. Conclusion Opioid-mediated analgesia causes a reduction and even a reversal of pain sensation, thus playing a significant role for the integrity of the human body. However, opioids can also cause hyperalgesic pain conditions in both animals and humans [29] and opioid therapy can be complicated by development of tolerance. Even after a short-term application, opioids have been shown to initiate sensitisation processes that are still detectable after several days [111,112]. Both, hyperalgesic effects and tolerance development could be explained by opioid-activated pronociceptive systems. Activation of these pronociceptive mechanisms could also underlie the lack of preemptive properties of opioids used clinically today [188—190] and has to be considered clinically in short-term application of opioids, but also in longer term opioid therapy. Combination of opioids with other classes of analgesics and opioid rotation can help to reduce sensitisation processes and optimise pain therapy, as opioids will keep their central role in postoperative, traumatic, or tumor pain therapy.

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