Chronic Pain

16 May

The use of opioids for chronic noncancer  pain (e.g., neuropathic  pain, mus- culoskeletal pain) is controversial.  Despite the fact that many patients  have received opioids chronically (Portenoy  et al. 1991), we do not really know how well they work. Opioid efficacy in musculoskeletal pain and neuropathic pain has been claimed in a number  of case reports  and uncontrolled  open studies. Few controlled  studies investigating the efficacy and side effects of opioids in these clinical settings are available (Caldwell et al. 1999; Moulin et al. 1996; Peloso et al. 2000; Watson  and  Babul 1998). At the  moment, the maximum  duration  of opioid  treatment  investigated  in a double-blind placebo-controlled  study is 9 weeks (Moulin et al. 1996). Most trials found a reduction  in subjective pain scores, but only one study examined  in de- tail much more important  parameters  such as psychosocial features, quality of life, drug dependence, and functional status (Moulin et al. 1996). No sig- nificant  improvements  in any of the latter  parameters  were detected,  and there was a lack of overall patient  preference  for the opioid. Most authors concluded  that  morphine  may confer analgesic benefit  with a low risk of addiction, but that it is unlikely to yield psychological or functional improve- ment (Watson and Babul 1998). Adverse opioid side effects were reported  in all of these investigations  and led to the drop-out  of large numbers  (up to 60%) of patients.  Thus, there is a lack of prospective controlled studies ex- amining the long-term  (at least several months)  administration of opioids. Future studies need to demonstrate  positive outcomes,  not only in subjec- tive pain reports, but, more importantly, also in terms of reduced depression, functional improvement,  reemployment  and decreased use of the healthcare system.

Many recent  studies  have focused on the activation  of opioid  receptors outside the CNS. One of the most extensively studied and most successful ap- plications is the intraarticular injection of morphine  (Kalso 2002). In dental surgery, peripheral antinociception  was detected after local morphine  appli- cation (Likar et al. 1998). In patients with chronic arthritis local morphine has also been shown to reduce pain and possibly inflammation  (Likar et al. 1997; Stein et al. 1999). The topical application of opioids produces antihyperalgesic effects when applied to painful ulcers and skin lesions, after burn  injuries, and in cutaneous pain (Kolesnikov et al. 2000; Krajnik et al. 1999; Long et al.

2001; Twillman et al. 1999). The local application of morphine in patients with corneal abrasion also showed analgesic effects (Peyman et al. 1994). Novel pe- ripherally restricted κ-agonists have been investigated in humans with chronic painful pancreatitis (Eisenach et al. 2003). In addition, some studies have sug-gested a relatively reduced development of opioid tolerance in inflamed tissue (Stein et al. 1996).



Almost all opioids are rapidly absorbed after oral administration and many undergo substantial first-pass metabolism in the liver. Much effort has been directed  at delaying absorption  with sustained-release  opioid  preparations because  adequate  duration  of analgesia  is a bigger clinical problem  than slow onset. Sometimes almost no absorption  is desirable: For example, lop- eramide and diphenoxylate  are potent  opioids used in the treatment  of di- arrhea  (and  recently  for topical  application)  because  they are  poorly  ab- sorbed and produce minimal effects in the CNS. Opioid drugs vary tremen- dously in their lipid solubility, and this largely determines  the efficiency of absorption  from peripheral  sites. For example, after sublingual administra- tion,  the bioavailability of morphine  is only 12%, while highly lipid solu- ble drugs like fentanyl and buprenorphine are 60%–70% absorbed  into the bloodstream  (Gong and Middleton  1992; Weinberg et al. 1988). Lipophilic opioids are now commercially available in buccal, intranasal,  and transder- mal preparations. Using a special nebulizer  apparatus,  it is possible to ad- minister morphine  by inhalation and achieve 63% bioavailability (Dershwitz et al. 2000).


All opioids are rapidly and extensively distributed  throughout the body. Af- ter a bolus intravenous  injection, the rapid increase and decrease in plasma

concentration looks quite similar for morphine  and fentanyl. The difference in onset and duration  of effect for these two drugs is a function of the rate at which plasma concentrations equilibrate  with those in brain,  at least in situations  where activation  of central  opioid  receptors  is the predominant mechanism of action (i.e., without major peripheral tissue injury). CNS con- centration of a lipophilic opioid like fentanyl closely follows the concentration in plasma, rising then falling rapidly as the drug is redistributed from highly perfused tissues into muscle and fat (Hug and Murphy 1979; Lotsch 2005b). Its short duration  is due to the rapidity of physical translocation  out of the CNS. In comparison,  the slow onset and offset of morphine  are because it enters and exits the CNS slowly. Brain concentrations of morphine  lag far behind those in plasma. When an opioid is administered  intrathecally or epidurally, the onset of effect is determined  by the rate at which the drug penetrates  to reach opioid receptors in the dorsal horn. Since little metabolism occurs in the CNS, the effects are terminated  by redistribution into blood vessels. Re- cent animal studies into the relative contribution of peripheral versus central opioid receptors indicate that, depending  on the presence and extent of tis- sue injury and on the types of opioid receptors  involved, up to 80% of an analgesic effect following systemic opioid administration may be mediated by peripheral  opioid receptors  (D. Labuz, S.A. Mousa, M. Schäfer, C. Stein, H. Machelska, submitted). Similar observations were made in human studies us- ing the peripherally restricted agonist morphine-6-glucuronide (Tegeder et al.

2003; Hanna et al. 2005).

Metabolism and Excretion

All clinically available opioids undergo extensive hepatic metabolism to polar metabolites that are excreted by the kidney (Lotsch 2005a). The notable ex- ception is remifentanil, which is rapidly hydrolyzed by nonspecific esterases in peripheral tissues and plasma (Servin 2003). In general, morphine  and its close congeners mainly undergo synthetic biotransformation to glucuronides, while meperidine and the fentanyl derivatives undergo oxidative metabolism by cytochrome  P450 enzymes. Both morphine  and fentanyl have high hep- atic extraction ratios (0.7 and 0.6, respectively). This means that the clearance of these drugs is sensitive to factors that alter liver blood flow. On the other hand, clearance is relatively unaffected by inducers or inhibitors  of liver en- zymes. The major  metabolite  of morphine  is the 3-glucuronide,  but about 15% forms morphine 6-glucuronide (M6G), a compound that has substantial opioid agonist activity (Kilpatrick and Smith 2005). It is likely that this highly

polar metabolite does not easily enter the CNS (Portenoy et al. 1991) but may produce analgesia via peripheral opioid receptors (Hanna et al. 2005; Tegeder et al. 2003).

Side Effects

Acute Opioid Application

Cardiovascular System

High doses of morphine, fentanyl, sufentanil, remifentanil, and alfentanil are associated  with a vagus-mediated  bradycardia.  Severe bradycardia  or even asystole is possible, especially in conjunction  with the vagal stimulating  ef- fects of intubation  (Bowdle 1998). With the exception of meperidine, opioids do not  depress  cardiac  contractility.  Arterial blood  pressure  often falls as a result  of bradycardia  and  decreased  sympathetic  reflexes. However, opi- oids have depressant  effects in patients  with congestive heart failure (Liang et al. 1987) and in myocardial ischemia/reperfusion-induced arrhythmias (Lee

1992). Recent evidence has also implicated opioids as having cardioprotec- tive effects (“ischemic preconditioning”), in that  tissue damage after brief

periods of coronary artery occlusion was prevented by opioids (Schultz et al.

1997). Suggested mechanisms  include the activation of mitochondrial  ATP- sensitive K channels (KATP channels)  in cardiomyocytes.  Opening of mito- chondrial  KATP channels is thought  to be protective by preservation  of mi- tochondrial  integrity, by dissipation  of mitochondrial  membrane  potential, and consequent reduction of calcium overload and apoptotic cell death (Cao et al. 2005; Cao et al. 2003). In isolated cardiomyocytes  as well as sympa- thectomized  intact  rat hearts,  it was suggested that  opioid  receptors  func-

tionally and physically crosstalk with β-adrenergic receptors, including het- erodimerization of these receptors, counterbalance  of functionally opposing

G protein  signaling, and interference  with downstream  signaling events. As a result, the β-adrenergic receptor-mediated positive inotropic  effect and an increase in cAMP are markedly attenuated  after opioid receptor  activation (Pepe et al. 2004).

Respiratory System

Respiratory depression is the adverse effect most feared by clinicians. These effects are mediated  by μ- and δ-receptors through  the direct inhibition  of rhythm-generating respiratory neurons in the pre-Boetzinger complex (PBC) of the brainstem (Manzke et al. 2003). Opioids produce a dose-dependent de-

pression of the ventilatory response to hypercarbia and hypoxia (Ladd et al.

2005; Weil et al. 1975). Respiratory depressant  effects may be detectable well before clinically apparent changes in respiratory rate and depth. With increas- ing opioid doses, respiratory  rate slows and tidal volume initially increases

and then eventually decreases. High doses can produce  apnea, and a small number of patients still die each year from opioid-induced respiratory depres- sion. The potential  is greatest in heavily co-medicated  (e.g., with sedatives) patients  who are unstimulated  and unmonitored. In a classic study, Forrest and Belleville showed that natural sleep greatly increases the respiratory  de- pressant effects of morphine (Forrest and Bellville 1964). Fentanyl, alfentanil, and sufentanil have all been reported  to produce “recurrent”  respiratory  de- pression in postoperative  patients who initially seemed to be breathing well (Becker et al. 1976). It seems likely that these episodes were actually due to variations in the level of postoperative (e.g., nociceptive) stimulation. Recently it was shown that serotonin 4(a) [5-HT4(a)] receptors are expressed in respira- tory PBC neurons, their selective activation protects spontaneous  respiratory activity, and 5-HT(4a) receptors and μ-receptors affect the intracellular con- centration  of cyclic AMP in opposite ways (Manzke et al. 2003). Treatment of rats with a 5-HT4 receptor-specific agonist prevented fentanyl-induced  respi- ratory depression without loss of fentanyl’s analgesic activity (Manzke et al.

2003). These findings might stimulate novel therapeutic  developments in the future (Eilers and Schumacher 2004).


Sedation  is a frequent  and  serious  side effect of opioid  analgesics, some- times reported as fatigue or tiredness by patients (Shaiova 2005). Importantly, small subanalgesic doses of opioids can multiply the sedative potency of mi- dazolam (Kissin et al. 1990). Similar interactions  have been demonstrated with propofol (Short et al. 1992) and barbiturates.  Thus, for the clinician it is important  to remember  that patients  receiving multiple sedative medica- tions  simultaneously  are at increased  risk and need to be monitored  ade- quately.

Nausea and Vomiting

Opioids stimulate  nausea and vomiting by a direct effect on the chemore- ceptor trigger zone in the area postrema in the brainstem  (Apfel et al. 2004; Wang and Glaviano 1954). This effect is increased by labyrinthine  input, so patients  who are moving are much more likely to be nauseated  than those lying quietly. Prophylactic antiemetic interventions  include the avoidance of other emetogenic drugs (e.g., inhalational  anesthetics)  by total intravenous anesthesia (e.g., with propofol). Serotonin antagonists,  dexamethasone,  and droperidol  can be used to treat opioid-induced  nausea and vomiting (Apfel et al. 2004).

Cough Suppression

Opioids depress  cough by direct  effects on medullary  cough centers  (e.g., raphe nuclei; Chou and Wang 1975; Schug et al. 1992). The structure-activity requirements  for the antitussive  effects are not the same as those for typi- cal μ-receptor-mediated analgesic effects. The greatest activity is seen with drugs  like codeine and  heroin—morphine congeners  with bulky substitu- tions at the 3 position.  The stereospecificity of the response  is different as well: cough suppression  is produced  by dextroisomers  of opioids (e.g., dex- tromethorphan) that do not have analgesic activity (Chung and Chang 2002; Lal et al. 1986).


Pupil Constriction

The miotic effect of opioids occurs through a direct action on the autonomic (Edinger–Westphal) nucleus of the oculomotor nerve to increase parasympa- thetic tone. This effect can be detected after extremely small (subanalgesic) doses. Relatively little tolerance occurs to this effect, so even patients taking very high doses of opioids for extended periods of time (e.g., for chronic cancer pain) will continue to have constricted pupils. Pupil responses have proved use- ful for simultaneous pharmacokinetic–pharmacodynamic modeling of opioids (Zacny 2005).


Skeletal Muscle Rigidity

This phenomenon, often incorrectly termed “truncal” or “chest wall” rigidity, is actually a generalized hypertonus  of striated muscle throughout  the body (Benthuysen et al. 1986). It is usually seen when potent opioids are administered rapidly (e.g., during induction of anesthesia) and is most commonly produced by fentanyl and its congeners (Bowdle 1998). The mechanism appears to be an

inhibition  of striatal γ-aminobutyric acid (GABA) release and an increase in dopamine production (Costall et al. 1978). Selective antagonism at the nucleus

raphe magnus in the rat can completely prevent the increase in muscle tone

(Weinger et al. 1991). During induction of anesthesia, opioid-induced  muscle rigidity can render a patient difficult to ventilate. Some authors have claimed that the problem does not seem to be loss of chest wall compliance but rather hypertonus of the pharyngeal and laryngeal musculature leading to narrowing of the laryngeal inlet (Arandia and Patil 1987; Bowdle and Rooke 1994). When rigidity is recognized, it must be treated with a muscle relaxant or reversed with naloxone.

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