Side Effects of Intrathecal and Epidural Opioids

891

Review Article Side effects of intrathe- Mark A. Chancy MD cal and epidural opioids

The purpose of this article is to review the literature on the condaires classiques sont le prurit, les nausdes et les vomis- side effects of intrathecal and epidural opioids. English-language sements, la rktention urinaire et ia ddpression respiratoire; ce articles were identified through a MEDLINE search and ne sont toutefois pas les seuls effets secondaires rapport~s. La through review of the bibliographies of identified articles. With plupart ddpendent de la dose et sont plus frrquents lorsque the increasing utilization of intrathecal and epidural opioids le morphinique est administr~ par la voie sous-arachno~dienne. in humans during the 1980s, a wide variety of clinically relevant Les effets second_aires surviennent moins souvent chez lea pa- side effects have been reported. The four classic side effects tients exposds de fafon chronique ~ des morphiniques sous- are pruritus, nausea and vomiting, urinary retention, and res- arachnoi'diens, 6piduraux ou systdmiques. Quelquevuns des ef- piratory depression. Numerous other side effects have also been fets secondaires rrsultent .de l'interaction de r~cepteurs morphi- described. Most side effects are dose-dependent and may be niques sprcifiques mais pas tous. Les auteurs concluent que more common if the opioid is administered intrathecaily. Side Hntroduction des morphiniques sous-arachno?diens et dpidu- effects are less common in patients chronically exposed to either raux reprrsente la pere~e la plus importante des deux dernib.res intrathecal, epidural, or systemic opioids. Some side effects are drcennies dans le domaine du traitement de la douleur. Ce- mediated via interaction with specific opioid receptors while pendant, des effets secondaires multiples de nature non- others are not. It is concluded that the introduction of intrath- nociceptive sont susceptiblea de survenir. Tous lea mkdecins ecal and epidural opioids marks one of the most important utilisateurs de morphinique sous-arachnoMiens et ~piduraux breakthroughs in pain management in the last two decades. doivent connattre ces effets secondaires qui sont mineurs pour However, a wide variety of clinically relevant non-nociceptive la plupart, alors que d'autres sont potentiellement idtaux. side effects may occur. All physicians utilizing intrathecal and epidural opioids must be aware of these side effects, for while most are minor, others are potentially lethal. Pure antinoeiception without side effects has long been an elusive goal. In the 1970s, the discovery of highly spe- Ce travail constitue un survol de la litt$rature portant sur les cific opioid receptors in the central nervous system, in effets secondaires des morphiniques sous-arachnogdiens et ~pi- particular their existence in the spinal cord, created new durau:c. Les articles en langue anglaise ont ~t~ identifids grace enthusiasm for the possible realization of this goal. Sub- ?: une recherche sur Medline et une revue des bibliographies sequent demonstration that small amounts of intrathecal des articles trouv$s de cette fafon. Avec l'utilisation croissante or epidural opioids produced profound antinociception des morphiniques sous-arachno~diens et ~piduraux d$but6e only heightened enthusiasm. However, with increasing clans les anr~es 80, on a d~crit avec pertinence une grande universal application of the technique in humans in the varidt6 d'effets secondaires convaincants. I_~ quatres effets se- 1980s, a wide variety of clinically relevant non-nocieeptive side effects have been reported, t,2 Because of the profound antinociception obtained and despite the non-nociceptive Key words side effects, spinal application of opioids remains very ANALGESIA: postoperative; popular and effective in the treatment of many pain states. ANALGESIA: morphine, fentanyl, sufentanil. Opioids are perhaps the oldest and most studied of From the Department of Anesthesiology, Foster G. MeGaw drugs. Opium use, for its euphoric effects, can be traced Hospital, Loyola University Medical Center, 2160 South First back over 4000 yr and its respiratory depressant effects Avenue, Maywood, Illinois 60153. were first noted approximately 600 yr ago. It was not Address correspondence to: Dr. Mark A. Chaney, until 1971, however, that highly specific opioid receptors Department of Anesthesiology, Foster G. MeGaw Hospital, were discovered. 3 In 1973, opioid receptors were localized Loyola University Medical Center, 2160 South First Avenue, in mammalian brain 4 and in 1976 they were found to Maywood, Illinois 60153. exist in primate spinal cord. s Also in 1976, Yaksh and Acceptedfor publication 9th June, 1995. Rudy first demonstrated the effectiveness of intrathecal

CAN J ANAESTH 1995 / 42:I0 / ppS91-903 892 CANADIAN JOURNAL OF ANAESTHESIA opioids in abolishing experimental pain in an animal TABLE I Side effects of intratheeal and epidural opioids model. 6 In 1979, initial reports of intrathecal 7 and epi- Pruritus dural s use of morphine in humans appeared in the lit- Nausea and vomiting erature. Urinary retention Intrathecal and epidural opioids produce profound seg- Respiratory depression mental antinociception in doses much smaller than would Mental status changes be required for comparable antinociception if adminis- Central nervoussystem excitation Hyperalgesia tered systemically. Antinociception may be prolonged; Herpes simplex labialis virus reactivation when morphine is utilized, it may persist for days fol- Neonatal morbidity lowing a single injection. 9 Unlike the response to local Sexual dysfunction anaesthetics, there is no motor, sensory, or autonomic Ocular dysfunction blockade. Paralysis and hypotension, therefore, are ab- Gastrointestinaldysfunction Thcrmoregulatorydysfunction sent. Another critical advantage over local anaesthetics Water retention is the availability of a specific opioid receptor antagonist, Cardiac dysrhythmia naloxone. Hair loss Neurotoxicity Phmnacokinefics of intmthecal and epidural opioids Anaphylaxis Side effects of intrathecal and epidural opioids are caused by presence of the drug in either cerebmspinal fluid or blood. Therefore, following administration of intrathecal and epidural opioids, side effects will be profoundly af- for elimination. Zs The terminal elimination half-life of fected by their pharmacokinetic behaviour. Fentanyl and morphine in cerebrospinal fluid is similar to that in sufentanil are, respectively, approximately 800 and 1600 plasma, two to four hours. 10,17 times as lipid-soluble as morphine. When administered Epidural administration of opioids also produces con- intrathecally or epiduraUy, therefore, morphine will ex- siderable cerebrospinal fluid concentrations of drug. hibit slower onset and longer duration of antinociception Penetration of the dura is considerably influenced by li- and a higher incidence of some side effects. pophilicity, but molecular weight may also play an im- Intratheeal administration of opioids immediately pro- portant role. 19 Following epidural administration, cere- duces high cerebrospinal fluid concentrations of drug that brospinal fluid concentrations of fentanyl peak in 10 to are dose-dependent.~~ Vascular reabsorption of opioids 20 rain 2~ while sufentanil concentrations peak in about following intrathecal administration does occur to some six minutes. 21 In contrast, cerebrospinal fluid concentra- degree, but is clinically irrelevant, n-13 Fentanyl and su- tions of morphine, following epidural administration, fentanil penetrate the spinal cord quickly, leaving little peak in one to four hours. ~,z3 Furthermore, only about drug to ascend cephalad in cerebrospinal fluid. In con- 3% of the dose of morphine administered epidurally Wast, morphine penetrates the spinal cord slowly, allowing crosses the dura to enter cerebrospinal fluid.Z~ The epi- considerable amounts of drug to ascend cephalad in cere- dural space contains an extensive venous plexus. There- brospinal fluid. Following lumbar intrathecal morphine fore, vascular reabsorption following epidural administra- administration, appreciable cervical cerebrospinal fluid tion of opioids is extensive. Epidural administration of eoneentrations occur one to five hours after injection, morphine, fentanyl, or sufentanil produces opioid blood while cervical cerebrospinal fluid concentrations of a concentrations that are similar to an intramuscular in- highly lipophilic opioids, similarly administered, are min- jection of an equivalent dose. Following epidural admin- imal. 14.15 The underlying cause of ascension of morphine istration, fentanyl blood concentrations peak at about five is bulk flow of eerebrospinal fluid. Cerebrospinal fluid to ten minutes ~;-s while sufentanll blood concentrations ascends in a cephalad direction from the lumbar region, peak even faster. =3~6 In contrast, blood concentrations of reaching the cisterna magna by one or two hours and morphine following epidural administration peak at about the fourth and lateral ventricles by three to six hours. 16 10 to 15 mill. ~7;s Although coughing, sneezing, or straining can affect movement of cerebrospinal fluid, body position does Side effects of intratheezd and epidural opioids not. 16 Highly lipophilic opioids are removed from cere- Side effects of intrathecal and epidural opioids are listed brospinal fluid rapidly secondary to vascular reabsorption in Table I. The four classic side effects are pruritus, nan- and spinal cord penetration. 17 In contrast, morphine per- sea and vomiting, urinary retention, and respiratory de- sists in cerebrospinal fluid for prolonged periods and may pression. Numerous other side effects have also been de- depend on reabsorption through arachnoid granulations scribed. In general, most side effects of intrathecal and Chancy: SPINAL OPIOIDS 893 epidural opioids are dose-dependent and may be more Opioid interaction in the substantia gelatinosa may thus common if the opioid is administered intrathecally. Side initiate an "itch reflex" through indirect action on the effects are less common in patients chronically exposed trigeminal nucleus. ~ Pruritus may be a clinical symptom to either intrathecal, epidural, or systemic opioids.29 Some in patients who experience sensory modulation disturb- side effects are mediated via interaction with specific ances; examples include multiple sclerosis, 4s diabetes, ~s opioid receptors while others are not. and differential neural blockade. 47

Pruritus Nausea and vomiting The most common side effect of intrathecal and epidural The incidence of nausea and vomiting following intrath- opioids is pruritus. It may be generalized but is more ecal and epidural opioids is approximately 30%. Al- likely to be localized to the face, neck, or upper thorax. 1,2 though the underlying mechanism is not related to sys- The incidence varies widely, from 0 to 100%, and it is temic absorption of drug, 31 the incidence of nausea and often elicited only after direct questioning. Severe pruritus vomiting following intravenous opioids is the same. l; is rare, occurring in only about 1% of patients. Pruritus Nausea usually occurs within four hours of injection and usually occurs within a few hours of injection and may vomiting soon thereafter. 31 The incidence may 3~ or precede the onset of anfinociccption. 3~ The incidence may not 32,5~be related to the dose of opioid administered may 32 or may not 3~ be related to the dose of opioid ad- and may be higher when intrathecal morphine is uti- ministered, may be higher when the intmthecal route is lized. J,2 Nausea and vomiting are more frequent in utilized 33 and is lower following subsequent doses. 29 Pru- women than in men experiencing pain. 50 Paradoxically, ritus is more likely to occur in obstetric patients32 which for reasons unknown, the epidural administration of may result from an interaction of oestrogen with opioid opioids may decrease the incidence of perioperative nau- receptors. 34,35 sea and vomiting. 51 Although opioids may liberate histamine from mast Nausea and vomiting induced by intrathecal and epi- cells, this does not appear to be the mechanism under- dural opioids are likely the result of cephalad migration lying pruritus. Opioids can produce naloxone-reversible of drug in cerebrospinal fluid and subsequent interaction pruritus without affecting plasma histamine concentra- with opioid receptors located in the area postrema. 39,52 tions. 36 Furthermore, rash following intrathecal and epi- Sensitization of the vestibular system to motion 53 and dural opioid administration is very rare. 37 Paradoxically, decreased gastric emptying34 produced by opioids may antihistamines may be effective treatment for pruritus, also play a role in nausea and vomiting induced by in- likely secondary to their sedative effects. Pruritus also trathecal and epidural opioids. does not .appear to be related to systemic absorption of opioid. 31 Urinary retention Pruritus induced by intrathecal and epidural opioids The incidence of urinary retention following intrathecal is likely due to cephalad migration of the drug in cere- and epidural opioids varies widely, from 0 to 80%, and brospinal fluid and subsequent interaction with the tri- occurs most often in young male volunteers. 2,3~ The in- geminal nucleus located superficially in the medulla. -38 cidence is not related to the dose of opioid adminis- Opioid receptors are present in the trigeminal nucleus tered 3~176 and may be higher when intrathecal mor- and trigeminal nerve roots.39 In fact, the most common phine is utilized. 33 The underlying mechanism is not location of induced pruritus is in the facial areas inner- related to systemic absorption of drug. 3~ Urinary reten- vated by the trigeminal nerve. 38 Animal studies support tion following intrathecal and epidural opioids is much the concept of an "itch centre" located in the lower me- more common than after intravenous or intramuscular dulla 4~ and indicate that the trigeminal nucleus is involved administration of equivalent doses of opioid. 55-57 in the itch reflex. 41 Injection of opioid into the cisterna Urinary retention induced by intrathecal and epidural cerebellomedullaris of eats promotes itching: ~ In hu- opioids is likely related to interaction with opioid recep- mans, naloxone has been used successfully in treatment tors located in the sacral spinal cord. 55 This interaction of intractable idiopathic pruritus 42 and cerebral tumours promotes inhibition of sacral parasympathetic nervous infdtrating the fourth ventricle cause itching in facial areas system outflow which causes detntsor muscle relaxation innervated by the trigeminal nerve: 3 and an increase in maximal bladder capacity leading to Altered central nervous system perception of pain may urinary retention. In humans, epidural morphine causes also play a role in pruritus induced by intrathecal and marked detrusor muscle relaxation within 15 rnin of in- epidural opioids. 44 The trigeminal nucleus descends into jection that persists for up to 16 hr and is readily reversed the cervical region of the spinal cord and becomes con- with naloxone. 5s Endogenous opioids likely play an im- tinuous with the substantia gelatinosa of the dorsal horn. portant role in normal control of bladder function via 894 CANADIAN JOURNAL OF ANAESTHESIA modulation of parasympathetic nervous system outflow TABLE II Factors increasing risk of respiratory depression at the sacral spinal cord level. 5s-6~ High doses of opioid Repeateddoses of opioid Respiratory depression Intratheealutilization The most feared side effect of intrathecal and epidural Morphine opioids is respiratory depression.62 Only four months after Intravenoussedatives initial utiliTation of intrathecal and epidural opioids in Advancedage Co-exiting disease humans, fife-threatening respiratory depression was re- Lack of opioid tolerance ported. 63-65 Clinically important respiratory depression Thoracic epidural placement has been reported following intrathecal morphine,66 epi- General anaesthesia dural morphine, s~ intrathecal fentanyl, 67 epidural fen- Increased intrathoracic pressure tanyl,68 intrathecal sufentanil, 69 and epidural sufentanil. 7~ Patient position Respiratory depression may occur within minutes of injection of opioid or may be delayed for hours. The incidence of respiratory depression depends on how it is ceptors exist in the ventral medulla and are important defmed. 71 The incidence of respiratory depression requir- in normal regulation of respiration. 79 Minute amounts ing intervention following conventional doses of intrath- of opioid directly applied to the medulla induce signif- ecal and epidural opioids is approximately 1%, which icant respiratory depression.S~ Following lumbar intrath- is the same as that following conventional dosing of in- ecal morphine administration, respiratory depression is tramuscular and intravenous opioids. 32.33,50,66,72 maximal when peak concentration of morphine is at- Early respiratory depression oceurs within two hours tained in the medulla..sl Delayed respiratory depression of injection of opioid. Most reports of clinically important characteristically occurs 6 to 12 hr following intrathecal early respiratory depression involve administration of epi- or epidural administration of morphine yet may persist dural fentanyl or epidural sufentani126,68,70,73,74and is very 24 hr. 30,76,77 rare following the intratheeal use of fentanyl or sufen- Detection of respiratory depression induced by intrath- tanil. 67,69 Respiratory depression induced by epidural fen- ecal and epidural opioids may be diftieult. Classic bra- tanyl and sufentanil likely results from systemic absorp- dypnoea may 33 or may not 72 be present and hypercarbia tion of drug, since blood concentration of opioid is may develop despite a normal respiratory rate. s2 Bradyp- proportional to the magnitude of respiratory depres- noea appears to be a more reliable clinical sign of early sion.26,73 However, cephalad migration of opioid in cere- respiratory depression following intrathecal or epidural brospinal fluid may also initiate early respiratory depres- use of fentanyl or sufentanil. 67,68,70,73 Pulse oximetry may sion. Following epidural administration of sufentanil, be valuable 3~ but must be interpreted cautiously if sup- cisternal cerebrospinal fluid concentrations of opioid are plemental oxygen is being administered, s3 The most re- measurable within one minute. 21 Apnoea within one min- liable clinical sign of respiratory depression appears to ute of injection of epidural sufentanil has been reported." be a depressed level of consciousness, possibly caused Although sensitive tests of respiratory depression reveal by hyperearbia.62.72,s2 Inhalation of carbon dioxide mix- that epidural morphine induces early respiratory depres- tures by healthy volunteers causes somnolence and loss sion, it is clinically irrelevant. 76,77 Clinically important of consciousness at PaCO2 of 80 mmHg.84 Character- early respiratory depression following intrathecal use of istically, early respiratory depression develops rapidly, morphine has never been described. whereas, delayed respiratory depression develops slowly Delayed respiratory depression occurs more than two and progressively) ~ Protocols for monitoring the devel- hours after injection of opioid. All reports of clinically opment of respiratory depression following intrathecal relevant delayed respiratory depression involve adminis- and epidural opioids vary among institutions. Most assess tration of intrathecal or epidural morphine.so,66 Clinically patients hourly for four to six hours if fentanyl or su- important delayed respiratory depression following a sin- fentanil has been administered and for 18 to 24 hr after gle injection of intratheeal or epidural fentanyl or sufen- morphine. 72 Clinically important respiratory depression tanil has never been described. However, continuous in- developing 24 hr after the last injection of intrathecal or fusions or repeated doses of a lipophilic opioid may epidural morphine has never been described. possibly initiate clinically relevant delayed respiratory de- Certain factors are known to increase the risk of res- pression. 73 Delayed respiratory depression results from piratory depression following intrathecal and epidural eephalad migration of opioid in cerebrospinal fluid and opioids (Table II). Concomitant use of any intravenous subsequent interaction with opioid receptors located in sedative increases the risk and should be avoided, if pos- the ventral medulla.VS High concentrations of opioid re- sible. Coughing may affect movement of cerebrospinal Chaney: SPINAL OPIOIDS 895 fluid 16 and may be associated with the development of opioids into the cerebral ventricles induces behavioural respiratory depression. 77 AlthOUgh body position does not excitation that is not reversible with naloxone. ~05,106 The affect movement of eerebrospinal fluid, 16 it may85 or may central nervous system excitation may be caused by the not 86 increase the risk of respiratory depression. Obstetric ability of opioids to block glycine or gamma-amino- patients appear to be at less risk for respiratory depres- butyric acid-mediated inhibition. 107 sion, perhaps because of increased blood concentration Although large doses of opioids reliably induce seizure of progesterone, a respiratory stimulant.87 activity in animals, clinically relevant doses of intravenous, intratheeal, or epidural opioids have never been Mental status changes observed to induce generalized cortical seizure activity Sedation, the most common mental status change fol- in humans. 96 lowing intrathecal and epidural opioids, occurs frequently with all opioids but is most commonly associated with Hyperalgesia the use of sufentanil. 88 The degree of sedation appears Paradoxically, large doses of intrathecal morphine will to be related to the dose of opioid administered. 30,49 Cen- cause hyperalgesia in laboratory animals. 103,J07-109Hyper- tral nervous system depression may be profound and algesia has also been reported in refractory cancer pain coma has been described. 89,s0 Any time sedation occurs patients administered large doses of intrathecal mor- following intrathecal or epidural administration of phine. 110,"I opioids, respiratory depression must be suspected. 9t Hyperalgesia caused by intrathecal morphine is not me- Mental status changes other than sedation may also diated by opioid receptors and is not affected by even occur after intrathecal and epidural opioids. Naloxone- large doses of naloxone, t03,107-109Alteration of spinal cord reversible paranoid psychosis 92 and catatonia 33,93 have coding of sensory information via a non-opioid receptor been reported. Others have described the development mechanism may play a role. 103.109 Hyperalgesia may be of euphoria, anxiety, and hallucinations. 66 caused by the ability of morphine to block glycine or Mental status change caused by intrathecal and epi- gamma-aminobutyric acid-mediated inhibition. 107,108 dural opioids likely results from cephalad migration of Conjugated metabolites of morphine, several hundred drug in cerebrospinal fluid and subsequent interaction times more potent at producing behavioural excitation, with opioid receptors located in the brain. Possible mech- may also be involved. ~~ Unlike morphine, opioids that anisms include interactions with opioid receptors located do not undergo conjugation are incapable of producing in the thalamus, limbic system, and cerebral cortex. 94 hyperalgesia. 38 Other behavioural changes may be caused by interaction with opioid receptors located in the amygdala. 39 Of in- Herpes simplex labialis virus reactivation terest, animal studies indicate that opioid receptors in the A link exists between the use of epidural morphine in brain may play a role in certain forms of mental illness. 95 obstetric patients and reactivation of herpes simplex labialis virus. 112,113Reactivation of the herpes virus typically Central nervous system excitation occurs two to five days after epidural administration of Tonic muscle rigidity resembling seizure activity is a well opioid, re,H4 Manifestation of symptoms characteristically known side effect of large doses of intravenous opioids. 96 occurs in the same sensory innervation area as the pri- Rarely, similar activity may be observed following ad- mary infection, which is usually facial areas innervated ministration of intrathecal or epidural opioids. Myoclonic by the trigeminal nerve. "3 A similar link between the activity following both intrathecal and epidural opioids use of intrathecal opioids in young patients and reac- has been reported. 97,98 Muscle rigidity has also been ob- tivation of the herpes virus has been suggested. ItS,H6 At served after administration of epidural morphine 93,99 and present, no evidence exists supporting a link between use intrathecal sufentanil, l~176Deep tendon reflexes may be- of any other opioid by any other route and reactivation come hypertonic following epidural morphine. ~~ In an- of herpes simplex labialis virus. 112 imals, large doses of intrathecal opioids induce hindlimb The underlying mechanism causing herpes virus reac- stiffness and rigidity. 102,103 tivation likely involves cephalad migration of opioid in The mechanism of central nervous system excitation cerebrospinal fluid and subsequent interaction with the caused by intrathecal and epidural opioids does not ap- trigerninal nucleus. 117 Reactivation of the herpes virus pear to be mediated by opioid receptors. 102 A spinal cord may be initiated by stimulation of opioid receptors lo- mechanism may be involved to4 but cephalad migration cated in the trigeminal nucleus, where the virus is known of opioid in cerebrospinal fluid and subsequent inter- to reside in latent form. jl3 Itching, with associated me- action with non-opioid receptors in the brainstem or basal chanical irritation of the skin, induced by intrathecal or ganglia is more likely. 96 In animals, administration of epidural opioids, may also indirectly reactivate the latent 896 CANADIAN JOURNAL OF ANAESTHESIA herpes viius. 112-114,1j7,118It is interesting to note that the secondary to an opioid-induced decrease in sympathetic most common areas of both pruritus and reactivation nervous system response to sexual stimulation. ~36 It ap- of herpes virus following intrathecal and epidural opioids pears that this effect occurs in the spinal cord, for sus- is in facial areas innervated by the trigeminal nerve. Phys- tained erection and inability to ejaculate is not observed iological changes normally associated with pregnancy, in- in males administered intravenous or intramuscular eluding depression of some aspects of cell-mediated im- opioids.55,134,J3s munity and alterations in hormone levels, may also be In female rats, intrathecal morphine inhibits while in- involved in reactivation of the herpes virus, tl8 Most likely, trathecal naloxone enhances sexual receptivity. ~35 Opioids the underlying mechanism causing herpes simplex labia- may also inhibit ovulation in rats. ~37 Amenorrhoea and lis virus reactivation is multifaetorial and may involve sterility are commonly observed in human female mor- all, some, or none of the above proposed mecha- phine addicts. 138 nisms. H3,Ha Ocular dysfunction Neonatal morbidity Naloxone-reversible nystagrnus has been reported follow- Neonatal morbidity is possible when intrathecal or epi- ing administration of intrathecal morphine 139 and epidural opioids are used in obstetric patients for pain relief dural morphine.14~ A naloxone-reversible M6ni~re-like during labour or Caesarean section. Following intrathecal syndrome has also been reported following administration or epidural administration of opioid to the mother, vas- of epidural morphine. 141 Vertigo has been observed after cular re,absorption of drug occurs. Once present in the use of epidural morphine, t42 The time course of symptom maternal blood, the opioid may then be transferred across development and the fact that they are naloxone- the placenta to the fetus. Immediately after birth, neonatal reversible indicate cephalad migration of opioid in cere- blood concentrations of opioid are detectable following brospinal fluid and subsequent interaction with opioid maternal administration of intrathecal morphine, H9 epi- receptors in the brain is likely involved. 14L142 dural morphine, 12~ epidural fentanyl, 121'j22 and epidural Like intravenous opioids, intrathecal and epidural sufentanil, lZ~ Clinically important respiratory depression opioids may initiate miosis. When miosis occurs following has developed in neonates following administration of epi- administration of intrathecal or epidural opioids, it in- dural morphine 12~ and epidural fentanyl m to the mother. dicates drug is present in cerebrospinal fluid at the mid- Furthermore, neurological signs of drug-induced depres- brain level and thus may be an early warning sign of sion in neonates have been observed following epidural impending respiratory depression. 143,z44 sufentanil, m However, multiple investgafions involving large numbers of patients have revealed that intrathecal Gastrointestinal dysfunction and epidural opioids are safe for the mother and neonate Intravenous and intramuscular opioids are known for provided that conventional doses are used. ~'Jl9'12Zm't~ 129 their ability to alter gastrointestinal motility. Intrathecal The use of intratheeal or epidural opioids in obstetric and epidural opioids may also delay gastric emptying and patients may affect the neonate in ways other than pla- prolong intestinal transit time. 54,102 In human volunteers, cental transfer of drug. For a variety of reasons, intrath- administration of epidural morphine delays gastric emp- ecal morphine may either inhibit 130.131 or enhance 132 the tying.145 In mice, intrathecal morphine causes dose- progress of labour. Following administration of epidural dependent, naloxone-reversible prolongation of small fentanyl or epidural sufentanil to obstetric patients, breast bowel transit time. ~ Patients administered intrathecal or milk concentration of opioid is negligible. 133 epidural opioids may exhibit signs and symptoms of ileus which may, in turn, lead to nausea and vomiting. 54'97'102'145 Sexual dysfunction The cause of the decrease in gastrointestinal motility fol- In healthy male volunteers, administration of epidural lowing intrathecal or epidural opioids is not related to morphine may lead to sustained erection and inability systemic absorption of drug 145 and appears to be caused to ejaculate. 55,1~ In male rats, intrathecal morphine in- by interaction with opioid receptors located in the spinal creases while intrathecal naloxone decreases the number cord. 145,146 of intromissions prior to orgasm. J35 These properties may make intrathecal or epidural opioids viable treatment op- Thermoregulatorydysfunction tions for premature ejaculation. 13s,136 Erection is under Opioids induce alterations in body temperature, an effect the influence of the parasympathetic nervous system that depends on species, route of administration, dosage, whereas ejaculation and termination of erection are under and ambient temperature. 147,14s In rats, intrathecal mor- the influence of the sympathetic nervous system. 136 There- phine causes a dose-dependent, naloxone-reversible in- fore, sustained erection and inability to ejaculate may be crease in body temperature, which appears to be caused Chaney: SPINAL OPIOIDS 897 by interaction with opioid receptors located in the spinal manifestations in these patients included sensory and cord. 149 However, alterations in body temperature may motor neurological dysfunction,33,]64myoclonic spasms, 97 also be initiated by cephalad migration of drug in cere- paresis, 33 and paralysis. 97 On the other hand, adminis- brospinal fluid and subsequent interaction with opioid tration of large doses of intrathecal morphine for pro- receptors located in the hypothalamus. In animals, ad- longed periods of time has proved to be safe. 29,j65,m66 In- ministration of opioid into the cerebral ventricles may trathecal morphine has been administered for as long as cause hyperthermia or hypothermia. 95,15~ In humans, 90 days and epidural morphine for as long as 450 days administration of epidural sufentanil may induce hypo- without problems. 29 Inadvertent overdose of epidural thermia, an effect likely caused by the ability of the opioid morphine has also occurred without sequela, t5s Post- to decrease shivering. 152-154 mortem examination of spinal cords from patients who had received prolonged infusions of intrathecal morphine Water retention revealed no damage. ~65 In summary, spinal cord damage Oliguria and water retention leading to peripheral oedema following administration of intrathecal or epidural opioids have been reported following administration of intrathecal may occur but is extremely rare if conventional doses and epidural morphine. 97,155 The water retention is likely of opioids are utilized. caused by release of vasopressin, stimulated by eephalad The spinal cord possesses only marginal blood flow migration of opioid in cerebrospinal fluid and subsequent and is susceptible to ischaemia if vasoconstriction occurs. interaction with opioid receptors located in the posterior Several studies have demonstrated opioid receptor- pituitary. The posterior pituitary does possess opioid re- mediated effects on blood vessels in vitro. 167 Although ceptors ~56 and release of vasopressin is stimulated in an- no studies have been performed in humans, it appears imals administered opioids. 157 In humans, administration from animal studies that intrathecal morphine does not of epidural morphine stimulates release of vasopressin de- affect spinal cord blood flow. i= spite effective analgesia. 155 Some opioid preparations contain preservatives which, if injected intrathecally or epidurally, may cause spinal Cardiac dysrhythmia cord damage. ~69,=70 In humans, inadvertent use of drugs New left bundle branch block has occurred in one patient with preservatives has caused paralysis following intrath- 45 rain after receiving an inadvertent overdose of epi- ecal 171 and epidural m injection. dural morphine. 15s Five minutes after intravenous naloxone, the left bundle branch block disappeared and the Anaphylaxis ECG reverted to the patient's usual pattern. True anaphylaxis foUowing administration of opioids, by any route, is extremely late. R has been reported once Hair loss following administration of epidural fentanyl. 1~3 A pre- Unexplained hair loss, resembling alopecia areata, has oc- vious exposure to fentanyl was documented and hyper- curred in one patient after receiving epidural morphine sensitivity was later confirmed by intradermal testing. for three days. 159 The hair loss was associated with wide- spread itching. Treatment and prophylaxis of side effects Essentially, all side effects of intrathecal and epidural Neurotoxicity opioids are mediated via opioid receptors. Treatment, Damage to the spinal cord may occur following admin- therefore, involves administration of an opioid receptor istration of intrathecal or epidural opioids. After intrath- antagonist, usually naloxone. The most common clini- ecal injection of morphine, 2.5 mg, the cerebrospinal fluid cally encountered side effects (pruritus, nausea and vom- concentration of drug is 4000 times that seen after intra- iting, urinary retention, respiratory depression) are all venous injection of 1.0 nag. kg -~. 160 In sheep, epidural readily antagonized with administration of naloxone. Un- morphine causes spinal cord necrosis 161 and intrathecal fortunately, when antagonizing side effects with naloxone, sufentanil induces inflammatory changes in the men- analgesia may 174-176 or may not 5~ be preserved. Ad- inges. 162 In cats, intrathecal sufentanil induces inflamma- ministration of an opioid agonist-antagonlst to treat side tory changes in the spinal cord. 103 Furthermore, these effects instead of an opioid antagonist may preserve anal- animals exhibited hindlimb dysfunction in the form of gesia, t79,~so During treatment of respiratory depression stiffness and weakness. 103,z61,m62In monkeys, however, no caused by intrathecal or epidural morphine, it may reap- spinal cord damage was detected following administration pear later if only a single dose of naloxone is ufiliTed,msl of intrathecal morphine. 163 In humans, intrathecal mor- Oral nalaexone, a long-acting opioid antagonist, may be phine 33'97'164 and epidural morphine 33 have been impli- useful if one wants to avoid the time and expense involved cated as possible causes of spinal cord damage. Clinical in maintaining a naloxone infusion. 182 Even though nal- 898 CANADIAN JOURNAL OF ANAESTHESIA oxone crosses the placenta, it appears to cause no neo- in primate spinal cord: distribution and changes after dorsal natal morbidity and thus may be utili7ed to treat side root section. Brain Res 1976; 112: 407-12. effects in obstetric patients. Is3 Drugs other than opioid 6 Yaksh TI., Rudy TA. Analgesia mediated by a direct spi- receptor antagonists have been used to treat side effects nal action of narcotics. Science 1976; 192: 1357-8. of intrathecal and epidural opioids with occasional sue- 7 WangJK, Nauss/_,,4, Thomas JE. Pain relief by intrathe- cess. Antiemetics are often useful in treating nausea and eally applied morphine in man. Anesthesiology1979; 50: vomiting yet unwanted sedation may aggravate respira- 149-51. tory depression. ~ 8 Behar M, Magora F, Olshwang D, Davidson JT. Epidural Prophylactic administration of opioid receptor antag- morphine in treatment of pain. 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