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Baclofen as an adjuvant analgesic
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Vol 9 No. 8 November 1994
Journal of Pain and Symptom Management
Baclofen as an Adjuvant Analgesic Gerhard
H. Fromm, MD+
Department ofNeurology, School of Medicine, Universi(y ofPittsbwgh, Pittsburgh, Pennsylvania
Abstmct Baclofen is a y-aminobutyric acid (GABA) agonist approved for the treatment of spasticity and commonly used in the management of many types of neuropathicpain. Controlled studies have demonstrated the efficacy of this drug in trigemiaal neuralgia. Although its pre&e mechanism of analgesic action is unknown, it is likely that a drug-induced increase in inhibitory activity k su&ient to interrupt the cascao? of neural events that culminates in aberrant activity of wide dynamic range neurons, or we rostra1 neurons in. nocicqbtive pathways, that is the substrate for some types of neun$athic pain. The optimal use of bachfen as an adjuvant analgesic requires an understanding of its pharmacology, side effect spectrum, and dosing guidelines that have #woven useful in clinical practice. Failure of baclofen therapy following a prolonged trial requires dose tapering to discontinuation due to the potential for a withdrawal syndrome. J Pain Symptom Manage 1994;9:500-509.
pior
Bactofm, adjuvant analgesic, neuropathic pain
Inhduction Opioid analgesics and nonsteroidal antiinflammatory drugs are currently the major classes of analgesic drugs. While efficacious, these drugs have a number of serious limitations. The opioids have undesirable side effects, including the possible development of physical dependency, cognitive changes, somnolence, and constipation. The nonsteroidal anti-inflammatorv drugs have a more limited analgesic potential, and may produce equally troublesome toxicities, such as peptic ulcer. These traditional analgesic classes are relatively less effective for neuropathic pain,1-4 which accounts for up to 25% of patients attending pain clinics5
*Deceased, January 7,1994. Address reprint requests to: Mrs. Ann Fromm, 1401 North Negley, Pittsburgh, PA 15206, USA. Acct$tedforpublication: November 23, 1993.
An alternative approach to the treatment of neuropathic pain would be to modify the sensory input to the central nervous system, thereby reducing the transmission of information related to the sensation of pain.” This could be accomplished by decreasing excitatory transmission or by increasing pre- or postsynaptic inhibitory mechanisms in the spinal cord and brainstem. There is considerable experimental and clinical evidence that neuropathic pain occurs when irritation or injury of peripheral nerves causes the development of ectopic neural pacemaker sites and the degeneration of inhibitory interneurons in the spinal cord and brainstem.‘ss The combination of increased afferent activity and impaired segmental inhibition results in the firing of widedynamic-range neurons at frequencies normally associated with noxious stimuli and the consequent conscious perception of pain. Excitatory input to these neurons is thought to be mediated by the excitatory amino aclds;“~rO yaminobutyric acid (GABA) and glycine are
Q U.S.Cancer Pain Relief Committee, 1994 Published by Elsevier, New York, New York
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the major inhibitor 1~~srnitters.l’ Excitatory amino acid antagonists and ~~A or glycine agonists could therefore be useful new analgesic agents, especially for the treatment of ueoropathic pain8 Baclofen is a GABA analogue that is able to cross the blood-brain barrier and has been sho&n to have an antinociceptive action in a variety of expe~men~l models. The intraperitoneal or subcutaneous administration of baclofen increases the response time of mice in the hot plate and tail flick tes&t2-*s and suppresses the aversive response induced by the microapplication of bradykinin onto rat tooth pulp.‘“tt7 Baclofen also has an antinociceptive effect when administered in~a~ecally,ts,‘~~ in~aven~icularly,2s or by microinjection into the brainstem.“t In contrast to this ove~vhelm~ng evidence of an experiemental antinociceptive action, the clinical experience has been that baclofen does not have an analgesic effect in most chronic pain conditions. For example, baclofen was not signiftcantly superior to placebo in postoperative dental pain”” and it failed to relieve postherpetic neuralgia or diabetic neuropathy pain in an open trial.2” Baclofen resembles carbamazepine and pbenytoin in its ability to depress excitatory transmission and facili~t~ segmental inhibition in the trigeminal nucleus,2425 with the L-enantiomer being more than five times as effective as the racemic mixture.2” In agreement with these laboratory findings, baciofen has proven to be effective in the treamlent of trigeminal neuralgia in several open clinical trials,ss37-~ as well as in a controlled doubleblind trial.31 Furthermore, L-baclofen was more than five times as effective as racemic baclofen in a double-blind crossover trial.“2 Baclofen has also been found to be effective in the treatment of glossopharyngeal or vagoglossopharyngeal neuralgia>S pretrigeminal neuralgia,s4 and episodic and allodynic pains in some patients with ophthalmic-postherpetic neuralgia2~ In contrast to the aforemen~oned negative trials, the preoperative intravenous or intramuscular admi~is~ation of baclofen has been reported to block the acute pain caused by diladon and curettage of the uten.&s and to prolong the analgesic effect of fentanyl in neurosurgic~ proceduresss Intrathecal administtation of baclofen has also been reported
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to suppress spontaneous and allodynic dysesthetic pain patients ~~tb spinal lesions.~+’
The discrepancy between baclofen’s marked an~nociceptiv~ effect in animal experiments,(i~12-20and its lack of analgesic action in most chronic pain conditions2*~~” underscores the problems involved in relating expz-imental pain to the pathological pain caused by disease or injury. Of late, the emphasis in neuroscience and in pain research has been on an increasinglyreductionist approach which extends down to the molecular level. These techniques have produced major advances in our understanding of the normal and abnormal functioning of the netl;ous system. Molecules and receptor complexes, however, cannot experience pain. Driven to its ultimate conclusion, a purely molecular approach would be akin to an attempt to elucidate the greatness of “Hamlet” by analyzing the content of the ink and paper used by Shakespeare. As we proceed from behavioral observations in awake animals to recording in viva then on to recording from tissue slices and cultured neurons, and eventually to patch clamping of single channels and investigation of receptor structure, we progressively increase the precision of the measurements and control over the neurons’ environment. However, we simultaneously loose the connectivity of these neurons to the rest of the nervous system, which normally plays a large role in determining neuron behavior. We are thus confronted with a Biological Uncertainty Principle (Figure 1) akin to Heisenberg’s Uncertainty Principle.saSg Heisenberg’s Principle states that it is theore5cally impossible to simultaneously measure both the position and the velocity of an electron, as measuring either one disturbs the other. In studying the nervous system, increasing the precision of the measurement decreases the connectivity of the neurons under observation and vice versa. The constraints imposed by the inevitable trade-off between the precision of the measurement and the connectivity of the neuron to the rest of the CNS requires a synthesis and integration of the data provided by all the currently available techniques, from molecular
9lOLO~lCAL
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Behavioral obse?jalifns a6 3% =S
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PRlNCIPLE
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Record neufo;aclivity
in vivo
Rewrd neuron&3ctivity in slices Record neuron ylivity
Es_ z!z
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Record membrane actir(iUywith patch clamping Receptor&dir@
studies
Fig. 1. On going from behavioral observations in awake animals to recording single neuron activity in vivo, and on to recording from more and more isolated neurons in vitro, and eventually studying subcellular fragments, there is a progressive increase in the precision of the measurements but at the same time also a progressive decrease in the neuron’s connections to the rest of the nervous system. Adapted from Fromm (1992),sa with permission.
biology to behavioral observations of the whole animal. This will allow a real understanding of the mechanisms by which analgesic drugs exert their beneficial effect. This article will therefore endeavor to integrate the data provided by in vitro experiments with that derived from in vivo studies in an effort to obtain as accurate as possible a picture of how baclofen stops the attacks of trigeminal neuralgia and other episodic pains. Baclofen selectively activates GABA, receptors.4O~*rThere are both presynaptic and postsynapticGABA, receptors, and the binding of baclofen to these receptors is modulated. by G proteins.42-f4 ~tivation of presyna~tic GABA, receptors decreases calcium conductance,42*45-47 leading to a decrease in excitatory amino acid release.47-56 In the spinal cord there is a greater density of these receptors on the terminals of primary afferent fibers than on descending fiber terminals.57-60 Baclofen may also inhibit the release of substance P.61-s3 At postsynaptic GABA, receptors, baclofen increases po~sium conduc~n~e~4~l~~ producing slow inhibitory postsynaptic potentials.65*70‘* Recently there have been many reports of GABAa autoreceptors,73-84 but it is not certain that such GABAn autoreceptors are active in viva.” In the trigeminal nucleus, baclofen depresses neuronal response to electrical stimulation of the infraorbital nerve, increasing the latency of response and decreasing the number of spikes (Figure 2). In addition, baclofen markedly facilitates the segmental inhibition
elicited by delivering a condidoning stimulus to the infraorbital nerve 100 msec before the test stimulus.*41*5 The L-enantiomer of baclofen is more than five times as effective as racemic baclofens6 as l3-haclofen is a partial agonist at GABA, receptors and thus interferes with the action of Lhaclofens6 Transection of the spinal cord of the anterior third of the medulla blocks the antinociceptive effect of baclofen. This obs~c~on, and the finding that an antinociceptive effect can be demonstrated after the microinjection of baclofen into the brainstem or the cerebral ventricles, suggests that supraspinal sites are also involved in baclofen’s antinociceptive action.13~20*21.87 It has been suggested that this effect is mediated via descending noradrenergic, and possibly serotonergic, pathways.@-a1 Viewed collectively, all these obse~aeions suggest that baclofen prevents the occurrence of episodic and allodynic pain in humam&*” 33~31i~s6 and in experimental animalsss by means of two synergistic actions, one presynaptic and Fig. 2. Effect of baclofen on poststimulus histogram (16 stimuli at 0.5 Hx, I-msec bin width) of the response of a low-threshold mechanoceptive neuron in the trigeminal nucleus oralis to an unconditioned infraorbi~l nerve stimulus (US) and to stimulation of the infraorbital nerve 100 msec after a conditioning stimulus to the infraorbital nerve (3). Recordings were obtained just prior to an injection of baclofen (C) and 10 min after an injection of 1 mg/kg baclofen (BCF). N= total number spikes per histogram. Baclofen depressed the neuron response to the unconditioned stimulus to the infraorbital nerve and markedly enhanced the segmental inhibition. Adapted from Fromm and Terrence ( 1987),4s with permission. us
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one ~os~y~aptic. resy~apt~ca~~y, bac~of~n decreases calcium conductance and depresses the release of excitatory amino acids, espec~a~~~at primal ~er~nt terminals in the spinal cord and brainstem. Postsynaptically, baclofen increases po~sium conduc~nce leading to ~e~r~~al h~~o~~~~don. This comb~na~on of decreased excitatory ~nsrn~ss~~n and increased inhibition results in a marked facilitation of segmental inhibition. Segmental inhibition is an inhibitory feedback mechanism that sets the level of activity in sensory ~~~~_ enhancing such an i~ib~to~ mechanism would prevent the paroxysmal neuronal discharges associated with attacks of episodic and allodynic pain without impinging on normal levels of activity and normal sensation. Iln view of baclofen”s selective effect on episodic rather than ongoing pain, it is noteworthy that GABAa receptors appear to respond preferentially to phasic increases in GABA, while GABAt, receptors mediate tonic inhibitor mechan~sms”gs”94
Baclofen is relatively rapidly and almost completely absorbed after oral adminis~~~~.g~ A speciahzed transport mechanism for the intestinal absorption of baclofen has been demuns~ated in rats,96 Peak serum concentration is reached in about 2 hr but there is co~sid~~b~e Ruct~atior~ in plasma concentmtionP7 Baclofen is metabolized to only a limited extent and is primarily excreted by the kidneys in uncharged form, with 80% being eliminated in f day.g5 GIomerular fibration appears to be the dominant renal transport mechanism.9* The biologic half-life of bacbfen appears to be quite variable. Most studies have reported a half-life of approximately S-4 hr in the majority of patients, but calcuiations based on both plasma and urine data gave a h&We of almost 7 hr in one study.*
Adzme Eflects The most common side effects ofbaclofen are drowsiness, dizziness and gastrointestinal dis tress, The incidence of these s~ptoms can be reduced by starting with a very low dose and increasing this dose very slowly. About 10% of patients cannot tolerate baclofen because of one or more of these side effects. A rare complicadon of baclofen is an acute co~sion~ state that appears shortly after initiation of treatment and may be associated with periodic triphasic sharp
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wave elec~o~~c~~ba~o~m (PEG) ~atter~s.~~~ If8 This aheration in mental status clears up ~~~~p~y after ~isc~~t~~~~ng the drug. T&t-e have dso been sporadic reports of mania and depression, especially in patients wi psyc~ia~c history or those who doses (120 m~/day~ .I~~~l~~ Acute or chronic bacjlofen into~~~a~on can also cause an encephalopathy that has a benign outcome if actively managed.t”7-rtD The most common symptoms of acute intoxication are disturbance of conscious~e~ and/or seizures, ratory depression, muscular h~oto~~a, and mlized byporeflexia. Chronic intoxication usually causes hallucinosis, impaired memory, catatonia, or acute mania. Patients with renal disease may develop baclofen i~t~~icadon even with low doses as baclofen is mainly excreted by the kidneys.tilJt” The most important point to keep in mind with baclofen therapy is that it cannot be discontinued abruptly after prolonged use, as h~~uc~na~ons, manic psychodc episodes, or seizures may occur_11~*i9 If ~~d~~ symp terns occur, the previous dose of baclofen should be reinstituted and then g~du~ly reduced by 5-10 mg/day at weekly intervals.
As baclofen blocks episodic rather than ongoing types of pain, its main indication is for the treatment of~i~rn~n~ neural& p~~gern~n~ neuralgia, and ~ossoph~g~ or vagoglossopharyngeal neura.lgia.~~7~120~‘21 Baclofen abo ap pears to be effective in alleviating the allodynia and sharp, jabbing flashes of pain experienced by some patients with oph~~rni~-pos~erpe~c neuralgia. as The preoperative parented administration of baclofen has been reported to enhance the analgesic effect of fentanyl in therapeutic abortions”” and in some neurosurgical procedurcsss it is not clear if baclofen’s reported eEcacy in the treatment of acute low back syndromer’12 and in neurolep~c-induced “painful legs” syndrome’*3 represents a true analgesic effect or is secondary to ~aclofen’s antispastic action. On the other hand, Herman and colleaguess7 have reported that the intrathecal a~~is~don of baclofen suppresses both spon~neous and alfodynic dysesthetic pain in
vol. QNo. 8 A&???lber I994
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Diagnosis OfRJ
b
ElBCF
_a
Attacks persist
* Pain free
Fig. 3. Steps in the management of trigeminal neuralgia: TN, trigeminai neuralgia; BCF, baclofen; CBZ, carbamazepine; and MVD, micro\ascular decompression. From Fromm am! Tcrrence {1987) ,ss with permission.
+ * GE2 slowly 6 ~ecurf~nc% of l-H
I
8-J
Recurrence OfIN
b
I
patients with spinal lesions independently action on muscle spastic&y.
of its
Dosing Treatment of trigeminal neuralgia should start with baclofen, in view of its greater safety, even though it may not be quite as effective as
carbamazepine (Figure 3). The starting dose of baclofen is 5-10 mg three times a day. This dose is increased by IO mg every other day until the patient is pain free or side effects occur. The usual maintenance dose is W-60 mg/day in divided doses. Patients with severe trigeminat neuralgia may need to take baclofen at 3- to 4hr intervals because of its short biological half-life. The incidence of side effects from baclofen can be reduced by starting with a very low dose and increasing this dose slowly, but the severity of the attacks of trigeminal neuralgia usually preclude such a regimen. About 10% of patients cannot tolerate baclofen because of one or more side effects. The dose of baclofen should be gradually tapered after the patient has been pain-free for several weeks, because trigeminal neuralgia is characterized by exacerbations and remissions. If the painful paroxysms do not recur, the
patient can then remain without until the next exacerbadon.2
medication
is the next choice if baclofen is ineffective or causes unacceptable side effects. Due to the progressive increase in the severity of trigeminal neuralgia with time, neither baclofen nor carbamazepine monotherapy may eventually be able to control the attacks. As the combination of baclofen and carbamazepine is much more effective than either drug alone,“’ combination therapy with both drugs should be tried in those patients who do not respond to monotherapy. The combination of baclofen and phenytoin can be tried in patients who cannot tolerate carbamazepine, as baclofen also has a synergistic action with phenytoinst Those patients who become refractory to all these medications will require neurosurgical intervention. However, none of the currently available procedures is capable of providing permanent relief in all patients.7~‘24 It should therefore be noted that patients will often respond to another trial of medical therapy when their trigeminal neuralgia recurs after surgical intervention. Medical treatment with baclofen and carbamazepine should therefore As indicated
in Figure 3, carbamazepine
Ilot. 9 No. 8 November i 994 -.
Badofm
be tried once mm-e at this point, as outlined in Figure 3. The dosing of baclofen for the treatment of or ~~go~~ossopba~~gea~ neuralgia, pretrigeminal neusralgia, and the lancinating and allodynic pains of ophthalmicpostberpetic neuralgia is the same as for the treatment of ~~gern~na~ neuralgia.
Routes of Administration Baclofen is supplied in IO-mg and 2O-mg tablets. The IO-mg size is generally the more useful for the dearest of ~gemina~ and vagoglossopharyngeal neuralgia. In view of baclofen’s short half-life it is usually better to administer frequent small doses rather than larger doses at longer intervals. Baclofen is also available in single use ampules for intratbeca! administration in the management of severe spasticity of spinal cord origin in patients who are unresponsive to oral bac!ofen or experience in~oIe~ble side elects at effective oral doses.i25,i9fi As noted above, intrathecal baclofen may also have an analgesic effect in these patients.
The development of L-baclofen should represent a major advance in the medical treatment of trigeminal neuralgia and other disorders causing episodic or allodynic pain. As predicted by our laboratory obse~ations,?‘i*x’~ L-baclofen was more effective than five times as much mcemic baclofen in a double-blind frossover trial in patients with typical trigeminal neuralgia. 3s These patients also tolerated L-baclofen much better than racemic baclofen. L-baclofen therefore represents a significant improvement over racemic baclofen. Further controlled double-blind clinical trials of Lbaclofen in trigeminal neuralgia are currently underway. The reports that baclofen potentiates the analgesic effect of fentanyl in some gynecological and neurosurgical proceduress5*s6 suggest that further investigation of baclofen’s possible role as a preanesthetic medication is warranwd. Baciofen may make it possible to reduce the doses ofopioid, and the attendant potential side effects, in patients undergoing surgical procedures, if the encouraging results reported by Corli and colleagues35 and Panerai and col-
as Adjutant
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leagues”” are corroborated by additional triab.. Likewise. the possibility at intratbecaj baclofen may alleviate central pa as well as spasticity in some patinas with spina! cord lesiod7 deserves further clinical evaluation. Baclofen has been reported to reduce the biosynthesis and release of noradrenahnet” and to inhibit both the spontaneous and evoked activity of sympa~edc pre~flg~~or‘~c neurons in the spinal cord. ‘sa These observations suggest that baclofen may also be useful as an adjunctive medication in the treament of reflex sympathetic d~~~O~b~. The s~~a~e~ca~~y maintamed pain of reflex sympathetic dystrophy can often be alleviated by anesthetic block of the sympathetic ganglia innervating the painful bbckPar+> or by systemic a-adrenergic ade.‘~“~““’Baciofen’s proposed ability to reduce the production and release or nor-adrenaline and to inhibit the activity of sympathetic preganglionic neurons in the spinal cord could therefore also help to relieve this type of pain. and is worthy of appropriate chnical trials. The experiments by Losadars’ and by McKenna and SchrammtzX were conducted in vitro, and the cc ,lcen~dons of baclofen used were considerably higher than the plasma, cerebrospinal fluid, and tissue concentrations normally ac!hieved by the systemic administmtiot! of baclofen.““*‘ss It might therefore be necessary to administer baclofen i~t~~eca~~y, as is done for the treatment of severe spasticity,‘s”.r”” in order to alleviate sympathetically mantained pain.
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39. Fromm GH. Antiepileptic actions of valproate. In: Faingold CL, Fromm GH. eds. Drugs for the control of epilepsy: actions on neuronal networks involved in seizure disorders. Boca Raton, FL: CRC, ~992:45~461. 40. BOWS NG, Hill DR, Hudson AL, et al. Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature ~98~283:92-94. 41. Hill DR, Bowery NG. sH-baclofen and Z~H-GABA bind to bicuculline-insensitive GABA,$ sites in rat brain. Nature 1981;290:149-152. 42. Dolphin AC, McGuirk SM, Scott RH. An invesd~tion into the mechanisms of inhibitor of calcium channel currents in cultured sensory neurones of the rat by guanine nucleotide analogues and baclofen. Br J Pharmacol 1989;97:263-272. 43. Dutar, Nicoll RA. Pre- and postsynaptic GAB& receptors in the hippocamp~ have different pharmacological properties. Neuron 1988;1:585-591. 44. Thompsom SM, Gghwiler BH. Comparison of the actions of baclofen at pre- and postsynaptic receptors in the rat hippocampus in vitro. J Physiol ~992;451:3~-345. 45. Huston E, Scott RH, Dolphin AC. A comparison of the effect of calcium channel ligands and GABA, agonists and antagonists on transmitter release and somatic calcium channel currents in cultured neurons. Neuroscience 199~~721-729. 46. Lev-Tov A, Meyers DER, Burke RE. Activation of type B yaminobutyric acid receptors in the intact mammalian spinal cord mimics the effects of reduced presynaptic Caz+ influx, Proc Nat1 Acad Sci USA 198~85:533~5334. 47. Iosada ME, Acosta GB. Effects of baclofen on amino acid release. Eur J Pharmacol 1992;224:2125. 48. Ault B, Evans RH. The depressant action of baclofen on the isolated spinal cord of the neonatal rat. Eur J Pharmacol 1981;71:357-364. 49. Calabresi P, Mercuri NB, De Murtas M, Bernardi G. Endogenous GABA mediates presynaptic inhibition of spontaneous and evoked excitatory synaptic potentials in the rat neostriatum. Neurosci Watt 1990;188:99-102. 50. Davies J. Selective depression of synaptic excitation in cat spinal neurones by baclofen: an ionto phoretic study. BrJ Pharmacol1981;72:373-384. 51. Edwards FR, Harrison PJ, Jack JJB, Kullmann DM. Reduction by baclofen of monosynaptic EPSPs in lumbosacral motoneurones of the anesthetized cat. J Physiol 1989;416:539-556.
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52. Fox S, Krnjevic K, Morris E, Puil E, Werman R Action of baclofen on mammalian synaptic transmission. Neuroscience 1978;3:495-515,
67. Jarolimek W, Misgeld U. On the inhibitory actions of baclofen and ~arninobu9~~ acid in rat ventral midbrain culture. J Physioi 1992;451:41Q443.
53. Johnston GAR, Hailstone MH, Freeman CG. Baclofen: stereoselective in~bition of excitant
68. Newberry NR, Nicoll RA. Comparison of the action of baelofen with ~aminobu~c acid on rat
hippocampai pyramidal 1985;360:161-185.
cells in vitro. J PhysioI
69. Peet MJ, McLennan
H. Pre- and postsynaptic
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evoked h~erpolarization of CA1 hippocampal x-ones. ~xp Brain Res 1986;61:567-574.
neu-
70. ~arlsson G, OIpe H-R. Late inhibitory postsynaptic potentials in rat prefrontal cortex may be mediated by GABA, receptors. Experientia 1989; 45:157-158. 71. Morrisett RA, Mott DD, Lewis DV, Swartzwelder HS, Wilson WA. G~Aa-receptor-mediated inhibition of the N-methyl-D-aspartate component of synaptic transmission in the rat hippocampus. J Neurosci 1991;11:20~2~. 72. Newberry NR, NicolI RA. Direct hyperpolarizing action of baclofen on hippocampal p~an~idal cells. Nature 1984;3083450-452. 73. Baumann PA, Wicki P, Stierlin C, Waldmeier PC. investi~tious on GABA,~ receptor-mediated autoinhibition of GABA release. NaunynSchmiedebergs Arch Pharmacol 1990;341:88-93. 74. Bonanno G, Cavazzani P, Andrioli CC, Asaro D, Pellegrini G, Raiteri M. Release-regulating autore ceptors of the GABA&-type in human cerebral cortex. Br J Pharmacoll98~9~341-346.
83. Matt DD, Lewis DV, Ferrari CM, Wilson WA, Swartzwelder HS. Baclofen facilitates the develop ment of long-term potentiation in the rat dentate gyrus. Neurosci Lett 1990;113:222-226. 84. Waldmeier PC, Wicki P, Feldtrauer J-J, Baumann PA. Caz+-dependent release of endogenous GABA from rat cortical slices from different pools by different stimulation conditions. Naunyn Schmiedebergs Arch Pharmacol 1989;339:200-207. 85. Waldmeier PC, Wicki P, Bittiger H, ~aumann PA. The regulation of GABA release by GABA, autorereptors: some intoning fmdings and their possible implications. Pharmacol Commun 1992;2:&7. 86. Fromm GH, Shibuya T, Nakata M, Terrence CF. Effects of D-baclofen and L-baclofen on the trigeminal nucIeus. Neuropharmacology 1990;29:249-254. 87. Zorn S, Enna SJ. The effect of mouse spinal cord transection on the antinociceptive response to the yaminobutyric acid agonists THlP (4,5,6,7-tetrahydroisoxazoIo~5,4c]pyr~din~~o~ and baclofen. Brain Res 1985;~3~38~383. 88. Sawynok J. Monoamines as mediators of the antinocicepti~ effect of baclofen. Naunyn Schmiedebergs Arch Pharmacol1983;323:54-57. 89. Sawnok J, Dickson C. Evidence for the invoIvement of noradrenergic pathways in the antinociceptive effect of baclofen. Brain Res 1985;335:89-97.
75. Bonanno G, Pellegrini G, Asaro D, Fontana G, Raiteri M. GABAa autoreceptors in rat cortex synaptosomes: response under different depolarizing and ionic conditions. Eur J Pharmacol 198~17~41~9.
90. Sawynok J, Reid A. Role of ascending and descending noradrenergic pathways in the antino ciceptive effect of baclofen and clonidine. Brain Res 198~38~341-350.
76. Burgard EC, Santey JM. Long-lasting potentiation and epileptiform activity produced by GABA,, receptor activation in the dentate gurus of rat hippocampal slice. J Neurosci 1991;11:1198-1209.
91. Sawynok J, Reid A. Role of ascending and descending serotonergic pathways in the antino ciceptive effect of baclofen. Naunyn Schmiedebergs Arch Pharmacol 1988;337:359-365.
77. Davies CH, Davies SN, Collinridge GL. Pairedpulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses in rat hippocampus. J Physiol 1990;428:513-531.
92. Hao J-X, Xu X-J, ~dsko~us H, Seiger A, Wiesenfeld-Haliin Z. AIlodynia-like effects in rat after ischaemic spinal cord injury photochemically induced by laser irradiation. Pain 1991;45:175-185.
78. Deisz RA, Prince DA. Frequency-dependent depression of inhibition in guinea-pig neocortex in vitro by GABA, receptor feed-back on GABA release. J Physiol 1989;412:513-541.
93. Fromm GH, Sato K, Nakata M. The action of GABA,, antagonists in the trigeminai nucleus of the rat. NeuropharmacoIo~ 19992;31:475-480.
79. Giralt M”& Bonanno G, Raiteri M. GABA terminal autoreceptors in the pars compacta and in the pars reticulata of the rat substantia nigra are GABA,. Eur J Pharmacoll~~l7~137-1~. 80. Harrison NL. On the presynaptic action of baclofen at inhibitory synapses between cultured rat hippo~pal neurones. J Physioll~~42~43~~. 81. Harrison NL, Lange GD, Barker JL. Daclofen activates presynaptic GABA, receptors on GABkergic inhibitor neurons from embryonic rat hip pocampus. Neurosci lett 1988;85:105-109. 82. Mott DD, Bragdon AC, Lewis DV. Baclofen antagonizes post-tetanic disinhibition in the rat chtate gyrus. Neurosci I&t 1990;110:131-136.
94. Fromm GH, Sato K, Sun K. Differential roles of GABA,, and GABAA receptors in the rat trigeminal nucleus. 1993 (submitted for publication). 95. Brogden RN, Speight TM, Avery. Baclofen: a preliminary report of its pharmacolo~ca~ properties and therapeutic efftcacy in spasticity. Drugs 1974; 8:1-14. 96. Merino M, Peris-Ribera JF, Torres-Molina F, et al. Evidence of a specialized transport mechanism for the intestinal absorption of baclofen. Biopharm Drug Dispos 198~1~27~~7. 97. Wuis EW, Dirks MJ, Vree TB, Van der KIeijn E. Pha~acokinetics of baclofen in spastic patients receiving multiple oral doses. Pharm Weekbl [Sci] 199iD;12:71-74.
Vcl. 9 No. 8 November 1994
Bachfm2 as Adjurlant
98. Wuis EW, Dirks MJ, Termond EF, Vree TB, Van der Kkijn E. Plasma and urinary excretion Ainetics of oral baclofen in healthy subjects. Eur J Clin Pharmacol 1989;3?:81-84. 99. Abarbanel J, Herishanu a: Frisher S. Encephalc+ patby associated with baclofen. Ann Neural 1985; 17:617-618. 100. Hormes JT, Benarroch EE, Rodriguez M, ISlass OX? Periodic sharp waves in bac~ofe~-induced encephaiopathy. Arch Nemo1 1988;45:814815. 101. Lazzarino LG, Nicolai A, Valassi F. Acute transient cerebral intoxication induced by low doses of bactofen. Ital J Neurol Sci 1991;12:323-325. 102. Liu HC, Tsai SC, Liu n, Chi CW. Baclofeninduced frontal lobe syndrome: case report. Paraplegia 1991;29:554556. 103. Nowack WI, King JA. Triphasic waves and spike wave stupor. Clin Electroencephalogr 1992;23:100104. 104. Sommer BR, Petrides 6. A case of baclofeninduced psychotic depression. J Clin Psyckiatry 1992;53:211-212. 105. Stewart JX A case of mania associated with high-dose baclofen therapy.J Clin Psychopharmacol 1992;12:215-217. 106. Wolf ME, Almy G, Toll M, Mosnaim AD. Mania associated with the use of baclofen. Biol Psychiatry 1982;17:757-759. 107. lee T-H, Chen S-S, Su S-L, Yang Y-S. Baclofen intoxication: report of four cases and review of the literature. Clin Neuropharmacol1992;15:56-62. 108. Lipscomb DJ, Meredith TJ. Baclofen overdose. Postrad Med J lQ8~5~108-109. 109. May CR. Baclofen 1983;12:171-173.
overdose. Ann Emerg Med
110. Weissenborn K, Wilkens H, Hausmann E, Degen PH. Burst suppression EEG with baclofen overdose. Clin Neural Neu~su~ ~~1;93:?7~~. 111. Himmelsbach FA, Kohler E, Zanker B, et al. Baclofen in toxication in chronic hemodialysis and kidney transplantation. Dtsch Med Wochenschr 1992;117:733-737. 112. Parmar MS. Akinetic mutism after baclofen. Ann Intern Med 1991;115:499-500. 113. Arnold ES, Rudd SM, Kirshner H. Manic psychosis following rapid withdrawal from baclofen. Am J Psychiatry 198~137:146~1~7. 114. Barker 1, Grant IS. Convulsions after abrupt withdrawal of baclofen. Lancet 1982;23556-557.
509
117. Lees AJ, Clarke CR& Harrison MJ. HallucinaLancet 1977; 1:858.
tions after withdrawal of baclofen.
118. Stien R. ~al~uc~nat~ons after sudden ~~ithd~~~,a~ of baclofen. Lancet 1977;2:44-45. 119. Terrence CF, Fromm GH. Complications of bacfofen withdrawal. Arch Neural 1981;38:588-589. 120. Fromm GH. T~gemina~ and g~ossopha~gea~ neuralgia. In: Johnson RT, ed. Current therapy in neurological disease. Toronto: BC Decker, 1990:78_ 81. 121. Fromm GH. Neuralgias of the face and oral cavity. Pain Digest 1991;1:67-7’7. 9.22. Dapas F, Hartman SF, Martinez L, et al. Baclofen in the treatment of acute loiv-back SF drome: a double-blind comparison with placebo. Spine 1985; l&345-349. 123. Sandyk R. Neuroleptic-induced “painful legs and moving toes” syndrome: successful treatment with clonazepam and baclofen. Ital J Neurol Sci 1990;11:573-576. 124. Fromm GH, Sessle BJ. Summary and conclusions. In: Fromm GH, Se&e BJ, eds. Trigeminaf neuralgia: current concepts regarding pathogenesis and treatment. Boston: Buttenvorth-Weinemann, 1991:205-219. 125. Penn RI?, Kroin JS. Continuous intrathecal baclofen for severe spasticity. Lancet lQ85;2:125127. 126. Penn RD, Savoy SM, Corcos D, et al. Intrathecal baclofen for severe spinal spasticq. N Engl J Med 1989;32~1517-1521. 1S’i. bsada ME. Baclofen and noradrenergic function in the rat frontal cerebral cortex. Eur J Pharmacol 1991;197:93-98. 128. McKenna KE, Schramm LP. Baclofec inhibits sympathetic pr~ganglionic neurons in an isolated spinal cord preparation. Neurosci htt 1984;47:8.5-88. 129. Bonica JJ. Causalgia and other reflex sympathetic dystrophies. In: Bonica JJ, Liebeskind JC, Albe-Fessard DG, eds. Advances in pain research and therapy. NewYork: Raven, 1979:141-166. 130. Arn& S. Intravenous phentolamine test: diagnostic and prognostic use in reflex sympathetic dystrophy. Pain 1991;46:17-22. 131. Raja SN, Treede RD, Davis KD, Campell JN. Systemic alpha-adrenergic blockade with phentolamine: a diagnostic test for sympathetically maintained pain. Anesthesiology 1991;74:691-698.
115. Hyser CL, Droke ME. Status epilepticus after baclofen withdrawal. J Nat1 Ned Assoc 1984;76:533538.
132. Knutsson E, Lindbolm U, MPtensson A. Plasma and cerebrospinal fluid levels of baclofen fLioresa1)
116. Kofler M, Imis AA. Prolonged seizure activity after baclofen withdrawal. Neurology 1992;42:697.
at optimal therapeutic responses ir. spastic paresis. J Neurol Sci 1974;23:473-484.
Vol 9 No. 8 November 1994
Journal of Pain and Symptom Management
Baclofen as an Adjuvant Analgesic Gerhard
H. Fromm, MD+
Department ofNeurology, School of Medicine, Universi(y ofPittsbwgh, Pittsburgh, Pennsylvania
Abstmct Baclofen is a y-aminobutyric acid (GABA) agonist approved for the treatment of spasticity and commonly used in the management of many types of neuropathicpain. Controlled studies have demonstrated the efficacy of this drug in trigemiaal neuralgia. Although its pre&e mechanism of analgesic action is unknown, it is likely that a drug-induced increase in inhibitory activity k su&ient to interrupt the cascao? of neural events that culminates in aberrant activity of wide dynamic range neurons, or we rostra1 neurons in. nocicqbtive pathways, that is the substrate for some types of neun$athic pain. The optimal use of bachfen as an adjuvant analgesic requires an understanding of its pharmacology, side effect spectrum, and dosing guidelines that have #woven useful in clinical practice. Failure of baclofen therapy following a prolonged trial requires dose tapering to discontinuation due to the potential for a withdrawal syndrome. J Pain Symptom Manage 1994;9:500-509.
pior
Bactofm, adjuvant analgesic, neuropathic pain
Inhduction Opioid analgesics and nonsteroidal antiinflammatory drugs are currently the major classes of analgesic drugs. While efficacious, these drugs have a number of serious limitations. The opioids have undesirable side effects, including the possible development of physical dependency, cognitive changes, somnolence, and constipation. The nonsteroidal anti-inflammatorv drugs have a more limited analgesic potential, and may produce equally troublesome toxicities, such as peptic ulcer. These traditional analgesic classes are relatively less effective for neuropathic pain,1-4 which accounts for up to 25% of patients attending pain clinics5
*Deceased, January 7,1994. Address reprint requests to: Mrs. Ann Fromm, 1401 North Negley, Pittsburgh, PA 15206, USA. Acct$tedforpublication: November 23, 1993.
An alternative approach to the treatment of neuropathic pain would be to modify the sensory input to the central nervous system, thereby reducing the transmission of information related to the sensation of pain.” This could be accomplished by decreasing excitatory transmission or by increasing pre- or postsynaptic inhibitory mechanisms in the spinal cord and brainstem. There is considerable experimental and clinical evidence that neuropathic pain occurs when irritation or injury of peripheral nerves causes the development of ectopic neural pacemaker sites and the degeneration of inhibitory interneurons in the spinal cord and brainstem.‘ss The combination of increased afferent activity and impaired segmental inhibition results in the firing of widedynamic-range neurons at frequencies normally associated with noxious stimuli and the consequent conscious perception of pain. Excitatory input to these neurons is thought to be mediated by the excitatory amino aclds;“~rO yaminobutyric acid (GABA) and glycine are
Q U.S.Cancer Pain Relief Committee, 1994 Published by Elsevier, New York, New York
0885-3924/94/$7.00
Vol. 9 No. 8 November I994
Back$-n as Adjuvant
the major inhibitor 1~~srnitters.l’ Excitatory amino acid antagonists and ~~A or glycine agonists could therefore be useful new analgesic agents, especially for the treatment of ueoropathic pain8 Baclofen is a GABA analogue that is able to cross the blood-brain barrier and has been sho&n to have an antinociceptive action in a variety of expe~men~l models. The intraperitoneal or subcutaneous administration of baclofen increases the response time of mice in the hot plate and tail flick tes&t2-*s and suppresses the aversive response induced by the microapplication of bradykinin onto rat tooth pulp.‘“tt7 Baclofen also has an antinociceptive effect when administered in~a~ecally,ts,‘~~ in~aven~icularly,2s or by microinjection into the brainstem.“t In contrast to this ove~vhelm~ng evidence of an experiemental antinociceptive action, the clinical experience has been that baclofen does not have an analgesic effect in most chronic pain conditions. For example, baclofen was not signiftcantly superior to placebo in postoperative dental pain”” and it failed to relieve postherpetic neuralgia or diabetic neuropathy pain in an open trial.2” Baclofen resembles carbamazepine and pbenytoin in its ability to depress excitatory transmission and facili~t~ segmental inhibition in the trigeminal nucleus,2425 with the L-enantiomer being more than five times as effective as the racemic mixture.2” In agreement with these laboratory findings, baciofen has proven to be effective in the treamlent of trigeminal neuralgia in several open clinical trials,ss37-~ as well as in a controlled doubleblind trial.31 Furthermore, L-baclofen was more than five times as effective as racemic baclofen in a double-blind crossover trial.“2 Baclofen has also been found to be effective in the treatment of glossopharyngeal or vagoglossopharyngeal neuralgia>S pretrigeminal neuralgia,s4 and episodic and allodynic pains in some patients with ophthalmic-postherpetic neuralgia2~ In contrast to the aforemen~oned negative trials, the preoperative intravenous or intramuscular admi~is~ation of baclofen has been reported to block the acute pain caused by diladon and curettage of the uten.&s and to prolong the analgesic effect of fentanyl in neurosurgic~ proceduresss Intrathecal administtation of baclofen has also been reported
501
to suppress spontaneous and allodynic dysesthetic pain patients ~~tb spinal lesions.~+’
The discrepancy between baclofen’s marked an~nociceptiv~ effect in animal experiments,(i~12-20and its lack of analgesic action in most chronic pain conditions2*~~” underscores the problems involved in relating expz-imental pain to the pathological pain caused by disease or injury. Of late, the emphasis in neuroscience and in pain research has been on an increasinglyreductionist approach which extends down to the molecular level. These techniques have produced major advances in our understanding of the normal and abnormal functioning of the netl;ous system. Molecules and receptor complexes, however, cannot experience pain. Driven to its ultimate conclusion, a purely molecular approach would be akin to an attempt to elucidate the greatness of “Hamlet” by analyzing the content of the ink and paper used by Shakespeare. As we proceed from behavioral observations in awake animals to recording in viva then on to recording from tissue slices and cultured neurons, and eventually to patch clamping of single channels and investigation of receptor structure, we progressively increase the precision of the measurements and control over the neurons’ environment. However, we simultaneously loose the connectivity of these neurons to the rest of the nervous system, which normally plays a large role in determining neuron behavior. We are thus confronted with a Biological Uncertainty Principle (Figure 1) akin to Heisenberg’s Uncertainty Principle.saSg Heisenberg’s Principle states that it is theore5cally impossible to simultaneously measure both the position and the velocity of an electron, as measuring either one disturbs the other. In studying the nervous system, increasing the precision of the measurement decreases the connectivity of the neurons under observation and vice versa. The constraints imposed by the inevitable trade-off between the precision of the measurement and the connectivity of the neuron to the rest of the CNS requires a synthesis and integration of the data provided by all the currently available techniques, from molecular
9lOLO~lCAL
UNCE~TAI~Y
Behavioral obse?jalifns a6 3% =S
oa zn
PRlNCIPLE
on inlacl animal
Record neufo;aclivity
in vivo
Rewrd neuron&3ctivity in slices Record neuron ylivity
Es_ z!z
E#
in cu!lure~
Record membrane actir(iUywith patch clamping Receptor&dir@
studies
Fig. 1. On going from behavioral observations in awake animals to recording single neuron activity in vivo, and on to recording from more and more isolated neurons in vitro, and eventually studying subcellular fragments, there is a progressive increase in the precision of the measurements but at the same time also a progressive decrease in the neuron’s connections to the rest of the nervous system. Adapted from Fromm (1992),sa with permission.
biology to behavioral observations of the whole animal. This will allow a real understanding of the mechanisms by which analgesic drugs exert their beneficial effect. This article will therefore endeavor to integrate the data provided by in vitro experiments with that derived from in vivo studies in an effort to obtain as accurate as possible a picture of how baclofen stops the attacks of trigeminal neuralgia and other episodic pains. Baclofen selectively activates GABA, receptors.4O~*rThere are both presynaptic and postsynapticGABA, receptors, and the binding of baclofen to these receptors is modulated. by G proteins.42-f4 ~tivation of presyna~tic GABA, receptors decreases calcium conductance,42*45-47 leading to a decrease in excitatory amino acid release.47-56 In the spinal cord there is a greater density of these receptors on the terminals of primary afferent fibers than on descending fiber terminals.57-60 Baclofen may also inhibit the release of substance P.61-s3 At postsynaptic GABA, receptors, baclofen increases po~sium conduc~n~e~4~l~~ producing slow inhibitory postsynaptic potentials.65*70‘* Recently there have been many reports of GABAa autoreceptors,73-84 but it is not certain that such GABAn autoreceptors are active in viva.” In the trigeminal nucleus, baclofen depresses neuronal response to electrical stimulation of the infraorbital nerve, increasing the latency of response and decreasing the number of spikes (Figure 2). In addition, baclofen markedly facilitates the segmental inhibition
elicited by delivering a condidoning stimulus to the infraorbital nerve 100 msec before the test stimulus.*41*5 The L-enantiomer of baclofen is more than five times as effective as racemic baclofens6 as l3-haclofen is a partial agonist at GABA, receptors and thus interferes with the action of Lhaclofens6 Transection of the spinal cord of the anterior third of the medulla blocks the antinociceptive effect of baclofen. This obs~c~on, and the finding that an antinociceptive effect can be demonstrated after the microinjection of baclofen into the brainstem or the cerebral ventricles, suggests that supraspinal sites are also involved in baclofen’s antinociceptive action.13~20*21.87 It has been suggested that this effect is mediated via descending noradrenergic, and possibly serotonergic, pathways.@-a1 Viewed collectively, all these obse~aeions suggest that baclofen prevents the occurrence of episodic and allodynic pain in humam&*” 33~31i~s6 and in experimental animalsss by means of two synergistic actions, one presynaptic and Fig. 2. Effect of baclofen on poststimulus histogram (16 stimuli at 0.5 Hx, I-msec bin width) of the response of a low-threshold mechanoceptive neuron in the trigeminal nucleus oralis to an unconditioned infraorbi~l nerve stimulus (US) and to stimulation of the infraorbital nerve 100 msec after a conditioning stimulus to the infraorbital nerve (3). Recordings were obtained just prior to an injection of baclofen (C) and 10 min after an injection of 1 mg/kg baclofen (BCF). N= total number spikes per histogram. Baclofen depressed the neuron response to the unconditioned stimulus to the infraorbital nerve and markedly enhanced the segmental inhibition. Adapted from Fromm and Terrence ( 1987),4s with permission. us
Sf
8
MSEC
VOL.9 No. 8 November 1994
blncbfm as Adjutant
one ~os~y~aptic. resy~apt~ca~~y, bac~of~n decreases calcium conductance and depresses the release of excitatory amino acids, espec~a~~~at primal ~er~nt terminals in the spinal cord and brainstem. Postsynaptically, baclofen increases po~sium conduc~nce leading to ~e~r~~al h~~o~~~~don. This comb~na~on of decreased excitatory ~nsrn~ss~~n and increased inhibition results in a marked facilitation of segmental inhibition. Segmental inhibition is an inhibitory feedback mechanism that sets the level of activity in sensory ~~~~_ enhancing such an i~ib~to~ mechanism would prevent the paroxysmal neuronal discharges associated with attacks of episodic and allodynic pain without impinging on normal levels of activity and normal sensation. Iln view of baclofen”s selective effect on episodic rather than ongoing pain, it is noteworthy that GABAa receptors appear to respond preferentially to phasic increases in GABA, while GABAt, receptors mediate tonic inhibitor mechan~sms”gs”94
Baclofen is relatively rapidly and almost completely absorbed after oral adminis~~~~.g~ A speciahzed transport mechanism for the intestinal absorption of baclofen has been demuns~ated in rats,96 Peak serum concentration is reached in about 2 hr but there is co~sid~~b~e Ruct~atior~ in plasma concentmtionP7 Baclofen is metabolized to only a limited extent and is primarily excreted by the kidneys in uncharged form, with 80% being eliminated in f day.g5 GIomerular fibration appears to be the dominant renal transport mechanism.9* The biologic half-life of bacbfen appears to be quite variable. Most studies have reported a half-life of approximately S-4 hr in the majority of patients, but calcuiations based on both plasma and urine data gave a h&We of almost 7 hr in one study.*
Adzme Eflects The most common side effects ofbaclofen are drowsiness, dizziness and gastrointestinal dis tress, The incidence of these s~ptoms can be reduced by starting with a very low dose and increasing this dose very slowly. About 10% of patients cannot tolerate baclofen because of one or more of these side effects. A rare complicadon of baclofen is an acute co~sion~ state that appears shortly after initiation of treatment and may be associated with periodic triphasic sharp
503
wave elec~o~~c~~ba~o~m (PEG) ~atter~s.~~~ If8 This aheration in mental status clears up ~~~~p~y after ~isc~~t~~~~ng the drug. T&t-e have dso been sporadic reports of mania and depression, especially in patients wi psyc~ia~c history or those who doses (120 m~/day~ .I~~~l~~ Acute or chronic bacjlofen into~~~a~on can also cause an encephalopathy that has a benign outcome if actively managed.t”7-rtD The most common symptoms of acute intoxication are disturbance of conscious~e~ and/or seizures, ratory depression, muscular h~oto~~a, and mlized byporeflexia. Chronic intoxication usually causes hallucinosis, impaired memory, catatonia, or acute mania. Patients with renal disease may develop baclofen i~t~~icadon even with low doses as baclofen is mainly excreted by the kidneys.tilJt” The most important point to keep in mind with baclofen therapy is that it cannot be discontinued abruptly after prolonged use, as h~~uc~na~ons, manic psychodc episodes, or seizures may occur_11~*i9 If ~~d~~ symp terns occur, the previous dose of baclofen should be reinstituted and then g~du~ly reduced by 5-10 mg/day at weekly intervals.
As baclofen blocks episodic rather than ongoing types of pain, its main indication is for the treatment of~i~rn~n~ neural& p~~gern~n~ neuralgia, and ~ossoph~g~ or vagoglossopharyngeal neura.lgia.~~7~120~‘21 Baclofen abo ap pears to be effective in alleviating the allodynia and sharp, jabbing flashes of pain experienced by some patients with oph~~rni~-pos~erpe~c neuralgia. as The preoperative parented administration of baclofen has been reported to enhance the analgesic effect of fentanyl in therapeutic abortions”” and in some neurosurgical procedurcsss it is not clear if baclofen’s reported eEcacy in the treatment of acute low back syndromer’12 and in neurolep~c-induced “painful legs” syndrome’*3 represents a true analgesic effect or is secondary to ~aclofen’s antispastic action. On the other hand, Herman and colleaguess7 have reported that the intrathecal a~~is~don of baclofen suppresses both spon~neous and alfodynic dysesthetic pain in
vol. QNo. 8 A&???lber I994
Fromm
504
Diagnosis OfRJ
b
ElBCF
_a
Attacks persist
* Pain free
Fig. 3. Steps in the management of trigeminal neuralgia: TN, trigeminai neuralgia; BCF, baclofen; CBZ, carbamazepine; and MVD, micro\ascular decompression. From Fromm am! Tcrrence {1987) ,ss with permission.
+ * GE2 slowly 6 ~ecurf~nc% of l-H
I
8-J
Recurrence OfIN
b
I
patients with spinal lesions independently action on muscle spastic&y.
of its
Dosing Treatment of trigeminal neuralgia should start with baclofen, in view of its greater safety, even though it may not be quite as effective as
carbamazepine (Figure 3). The starting dose of baclofen is 5-10 mg three times a day. This dose is increased by IO mg every other day until the patient is pain free or side effects occur. The usual maintenance dose is W-60 mg/day in divided doses. Patients with severe trigeminat neuralgia may need to take baclofen at 3- to 4hr intervals because of its short biological half-life. The incidence of side effects from baclofen can be reduced by starting with a very low dose and increasing this dose slowly, but the severity of the attacks of trigeminal neuralgia usually preclude such a regimen. About 10% of patients cannot tolerate baclofen because of one or more side effects. The dose of baclofen should be gradually tapered after the patient has been pain-free for several weeks, because trigeminal neuralgia is characterized by exacerbations and remissions. If the painful paroxysms do not recur, the
patient can then remain without until the next exacerbadon.2
medication
is the next choice if baclofen is ineffective or causes unacceptable side effects. Due to the progressive increase in the severity of trigeminal neuralgia with time, neither baclofen nor carbamazepine monotherapy may eventually be able to control the attacks. As the combination of baclofen and carbamazepine is much more effective than either drug alone,“’ combination therapy with both drugs should be tried in those patients who do not respond to monotherapy. The combination of baclofen and phenytoin can be tried in patients who cannot tolerate carbamazepine, as baclofen also has a synergistic action with phenytoinst Those patients who become refractory to all these medications will require neurosurgical intervention. However, none of the currently available procedures is capable of providing permanent relief in all patients.7~‘24 It should therefore be noted that patients will often respond to another trial of medical therapy when their trigeminal neuralgia recurs after surgical intervention. Medical treatment with baclofen and carbamazepine should therefore As indicated
in Figure 3, carbamazepine
Ilot. 9 No. 8 November i 994 -.
Badofm
be tried once mm-e at this point, as outlined in Figure 3. The dosing of baclofen for the treatment of or ~~go~~ossopba~~gea~ neuralgia, pretrigeminal neusralgia, and the lancinating and allodynic pains of ophthalmicpostberpetic neuralgia is the same as for the treatment of ~~gern~na~ neuralgia.
Routes of Administration Baclofen is supplied in IO-mg and 2O-mg tablets. The IO-mg size is generally the more useful for the dearest of ~gemina~ and vagoglossopharyngeal neuralgia. In view of baclofen’s short half-life it is usually better to administer frequent small doses rather than larger doses at longer intervals. Baclofen is also available in single use ampules for intratbeca! administration in the management of severe spasticity of spinal cord origin in patients who are unresponsive to oral bac!ofen or experience in~oIe~ble side elects at effective oral doses.i25,i9fi As noted above, intrathecal baclofen may also have an analgesic effect in these patients.
The development of L-baclofen should represent a major advance in the medical treatment of trigeminal neuralgia and other disorders causing episodic or allodynic pain. As predicted by our laboratory obse~ations,?‘i*x’~ L-baclofen was more effective than five times as much mcemic baclofen in a double-blind frossover trial in patients with typical trigeminal neuralgia. 3s These patients also tolerated L-baclofen much better than racemic baclofen. L-baclofen therefore represents a significant improvement over racemic baclofen. Further controlled double-blind clinical trials of Lbaclofen in trigeminal neuralgia are currently underway. The reports that baclofen potentiates the analgesic effect of fentanyl in some gynecological and neurosurgical proceduress5*s6 suggest that further investigation of baclofen’s possible role as a preanesthetic medication is warranwd. Baciofen may make it possible to reduce the doses ofopioid, and the attendant potential side effects, in patients undergoing surgical procedures, if the encouraging results reported by Corli and colleagues35 and Panerai and col-
as Adjutant
505
leagues”” are corroborated by additional triab.. Likewise. the possibility at intratbecaj baclofen may alleviate central pa as well as spasticity in some patinas with spina! cord lesiod7 deserves further clinical evaluation. Baclofen has been reported to reduce the biosynthesis and release of noradrenahnet” and to inhibit both the spontaneous and evoked activity of sympa~edc pre~flg~~or‘~c neurons in the spinal cord. ‘sa These observations suggest that baclofen may also be useful as an adjunctive medication in the treament of reflex sympathetic d~~~O~b~. The s~~a~e~ca~~y maintamed pain of reflex sympathetic dystrophy can often be alleviated by anesthetic block of the sympathetic ganglia innervating the painful bbckPar+> or by systemic a-adrenergic ade.‘~“~““’Baciofen’s proposed ability to reduce the production and release or nor-adrenaline and to inhibit the activity of sympathetic preganglionic neurons in the spinal cord could therefore also help to relieve this type of pain. and is worthy of appropriate chnical trials. The experiments by Losadars’ and by McKenna and SchrammtzX were conducted in vitro, and the cc ,lcen~dons of baclofen used were considerably higher than the plasma, cerebrospinal fluid, and tissue concentrations normally ac!hieved by the systemic administmtiot! of baclofen.““*‘ss It might therefore be necessary to administer baclofen i~t~~eca~~y, as is done for the treatment of severe spasticity,‘s”.r”” in order to alleviate sympathetically mantained pain.
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Fi-omm
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