Drug Therapy
Drug Therapy
The lack of a complete understanding of the pathophysio-logic mechanisms underlying central pain has resulted in a trial and error approach to the pharmacotherapeutic treatment of central pain. Because of the complexity of this condition, it is likely that different drugs will target different components of the pathophysiological sequela, thereby making it difficult to evaluate a specific site of action. Different therapeutic strategies for the treatment of central pain are described below.
Drugs That Affect Amino Acids
Excitatory amino acids may mediate nociceptive and non-nociceptive input to thalamic nuclei and so are candidates for transmitter systems that could be involved in central pain. Chronic pain may involve NMDA-mediated mechanisms (e.g. sensitization); and for this reason, NMDA antagonists have been used. Although the oral use of dextro-methorphan is ineffective in the treatment of central pain, the use of subanesthetic doses of intravenous, subcutaneous, and more recently oral ketamine, a noncompetitive lowaffinity NMDA antagonist, seems promising. Ketamine is also effective in reducing the intensity of continuous pain following SCI and poststroke patients. The muopioid receptor agonist alfentanil produced similar effects that did not differ significantly from those of ketamine. Allodynia also is reduced markedly by both ketamine and alfentanil. Certain characteristics of central pain, such as hypersensitivity to innocuous stimuli, may be diminished by drugs that enhance inhibitory neurotransmission, for example, clonazepam and sodium valproate that are GABAa and GABAb agonists that facilitate GABA inhibition in the CNS.
The enhancement of inhibitory GABA mediated processes is also being explored by the use of intrathecal baclofen.163 The GABAb agonist baclofen has been shown to be effective in the relief of pain following brain and spinal cord lesions. Intrathecal midazolam, a GABAa agonist has also been successful in the treatment of central pain.
Lamotrigine, a novel oral antiepileptic drug with potent antiglutamatergic action, has been shown to produce beneficial effects from long-standing central pain.165 This drug is a use-dependent blocker of voltage gated sodium channels and inhibits pathologically released glutamate. Drugs such as lamotrigine and others modulating neurotransmitter systems such as GABA and norepinephrine could offer longstanding relief of chronic central pain. Yamamoto et allb found that 56.4% of poststroke patients responded to intravenous thiamylal, an ultrashort-acting barbiturate, which reportedly is effective in blocking the effects of excitatory ammo acids in synaptic transmission. The GABAa agonist propofol, an intravenous anesthetic agent acting as a GABAa agonist, can immediately but temporarily alleviate the allodynia and ongoing pain at subanesthetic doses89 and is believed to relieve central pain by interfering with a reverberating thalamocortical generator. Propofol, like barbiturates and other general anesthetics, acts on GABAa receptors, but, unlike barbiturates, potentiates glycinergic transmission and may inhibit excitatory glutamatergic conduction. Tasker reported that 73 and 82% of central pain patients following brain injury or SCI, respectively, received temporary relief of pain by intravenous thiopental sodium, a GABAa agonist.
In summary, it is suggested that antagonizing excitatory transmission or strengthening GABAergic inhibition in the CNS can partially or totally control different components of central pain, which supports the hypothesis that central pain of brain or spinal origin may involve unbalanced gluta-mate/GABA transmission in the CNS.
Antidepressant Drugs
In cases where depression may play a significant role in the clinical profile of central pain, the use of antidepressant drugs such as amitriptyline and imipramine may be effec tive in alleviating pain in some patients, and these are the drugs of choice regardless of pain origin. The general mechanism by which antidepressants relieve central pain is basically unknown. Although these drugs are thought to in fluence serotonergic, noradrenergic, cholinergic, and dopa minergic systems, more studies are needed to determine the precise role of these drugs in the treatment of central pain. Taub and Collins167 obtained significant reductions in pain by using amitriptyline and fluphenazine in patients with central pain following cordotomy, brainstem infarction cerebral infarction, and spinal cord lesions. Because nora-drenaline and serotonin modulate thalamic burst firing activity by acting on thalamic reticular and relay nuclei, the beneficial effects of amitriptyline on central pain may be lated to the properties of this drug on noradrenaline and se rotonin reuptake. Controlled studies of tricyclic antidepressants may determine whether this effect is related specifically to serotonin or noradrenaline.
Most information related to th pharmacotherapy of cen tral pain is related to tricyclic antidepressants, and those with nonselective profiles may be associated with greater efficacy. The most effective tricyclic has not been established, although using the treatment associated with diabeti pe ripheral neuropathy desipramine seemed as effective as amitriptyline. Comparing amitriptilyne and carbamazepine with placebo, Leijon and Boivie found that only amitriptyline has a significant effect on CPSP. The analgesic effects are not thought to be related to the antidepressant effects of amitriptyline. Instead, the effects are believed to result from the blockade of norepinephrine and serotonin reuptake. Amitriptyline may relieve both constant and lancinating pain as well as allodynia. Thus, the combined use of serotonin (fluoxetine) and norepinephrine (desipramine) reuptake inhibitors may offer therapeuti efficacy. Andersen et al achieved pain relief, with fluvoxamine but not citalopram, two selective reuptake inhibitor. Dietary supplement of D-tryptophan, a biochemical precursor of serotonin also may have a role in the treatment of chronic pain. Trazodone HC1 (a serotonin reuptake blocker) had no significant effects on central pain following SCI. Despite the relatively scant knowledge about the pathophysiology of central pain, two thirds of patients can be relieved by treatment with adrenergically active antidepressants, which suggests that noradrenergic receptors play a key role in central pain. In cases where antidepressants alone are not effective, relief may be gained by the addition of oral mexiletine. To obtain maximal effects from adrenergically active antidepressants, it is important not to loose time trying the effect of classic analgesics, which are virtually devoid of action in central and other neurogenic pains.
Adrenergics
The alpha-2 agonist clonidine is effective for neuropathic pain and is thought to work by modulating serotonin and norepinephrine release in the spinal cord. Although effective in reducing phantom limb pain and cancer pain, it has not been systematically evaluted in central pain. Propanolol was effective in enhancing the effects of the antidepressant doxepin in alleviating central poststroke pain.
Anticonvulsants
Although the mechanism of analgesic action is not well understood, anticonvulsants such as carbamazepine, phenytoin, and clonazepam have been used successfully in treating central pain. Generally these drugs are thought to decrease abnormal neuronal activity through an action on sodium channels (e.g., carbamazepine and phenytoin) or V facilitating GABA-mediated inhibition (e.g., clonazepan.
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Anticonvulsant drugs are effective for paroxysmal pain, stabbing pain, and hyperesthesia…
…Unfortunately, the side effects of these drugs
limit their long-term usefulness.
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Local Anesthetics
Anecdotal reports described the effects of mexiletine and lidocaine on central pain. Local anesthetics block sodium channels, thereby decreasing neural activity and thus reduce repetitive discharges in dysfunctional neuronal pools. The possible hyperexcitability of damaged nervous system has been responsible for the treatment of central pain with local anesthetic agents such as lignocaine and the oral analogue mexiletine. Attal and colleagues reported successful use of intravenous lidocaine in a double-blind, placebo controlled study in patients with central pain associated with stroke or SCI. The results showed lidocaine was significantly superior to placebo in reducing the intensity of spontaneous pain for up to 45 minutes after injection and significantly reduced the intensity of brush-induced allodynia and mechanical hyperalgesia. Sometimes central pain is relieved by proximal or distal local anesthetic somatosensory blockade, acting as a modulator or through circulatory absorption. Infusion of local anesthetics in the proximal, but not distal, stump in patients with pain of spinal origin results in a transient relief of pain suggesting the existence of a pain generating mechanism for abnormal sensation in the spinal cord.
Opioids
There is insufficient evidence either to support or to refute the efficacy of opioids for central pain. Kupers et al found that morphine significantly reduced the affective, but not the sensory, dimension of pain sensation (which tended toward increasing) in patients with neurogenic pain of central origin. In a few patients, the effects of intravenous pentothal and morphine were examined; 8 of 11 patients experienced pain reduction with pentothal, but none with morphine, findings that are in keeping with conclusions that pain is not dependent on opiate mechanisms. Tasker described 55% of patients with central pain of spinal cord origin who experienced diminished pain with intravenous morphine or fentanyl.
The apparent inconsistency of the effectiveness of opioids in central pain was addressed by Hammond, who stated that the ineffectiveness of opioids may be explained by the low amount of conventional doses, which actually may excite pathologically active cells found in the brain and spinal cord. Opioids also may act differentially on different components of pain.
Other Drugs
Calcium channel blockers may suppress ectopic neural activity and may prove to be effective in the treatment of central pain. One drug that has received significant attention in the treatment of central pain is the putative calcium-channel blocker gabapentin. Although the precise mechanism for the therapeutic efficacy is not well understood it was shown to be efficacious in the treatment of neuropathic pain, including that of central origin. Glutamate antagonists, specifically NMDA antagonists, have shown promise in the treatment of central pain. Other newer drugs may also offer hope for the effective treatment of central pain. In the future drugs with multiple targets such as agmatine, an NMDA antagonist and inhibitor of nitric oxide synthase, may prove to be beneficial for the treatment of central pain.