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- Pharmacology of antidepressants and pain mechanisms
- Antidepressants in neuropathic pain
Abstract: Neuropathic pain is due to lesion or dysfunction of the peripheral or central nervous system. Tricyclic antidepressants and anticonvulsants have long been the mainstay of treatment of this type of pain. Tricyclic antidepressants may relieve neuropathic pain by their unique ability to inhibit presynaptic reuptake of the biogenic amines serotonin and noradrenaline, but other mechanisms such as N-methyl-D-aspartate receptor and ion channel blockade probably also play a role in their pain-relieving effect. The effect of tricyclic antidepressants in neuropathic pain in man has been demonstrated in numerous randomised, controlled trials, and a few trials have shown that serotonin noradrenaline and selective serotonin reuptake inhibitor antidepressants also relieve neuropathic pain although with lower efficacy. Tricyclic antidepressants will relieve one in every 2–3 patients with peripheral neuropathic pain, serotonin noradrenaline reuptake inhibitors one in every 4–5 and selective serotonin reuptake inhibitors one in every 7 patients. Thus, based on efficacy measures such as numbers needed to treat, tricyclic antidepressants tend to work better than the anticonvulsant gabapentin and treatment options such as tramadol and oxycodone, whereas the serotonin noradrenaline reuptake inhibitor venlafaxine appears to be equally effective with these drugs and selective serotonin reuptake inhibitors apparently have lower efficacy. Head-to-head comparisons between antidepressants and the other analgesics are lacking. Contraindications towards the use of tricyclic antidepressants and low tolerability in general of this drug class – may among the antidepressants – favour the use of the serotonin noradrenaline reuptake inhibitors. A recent study on bupropion, which is a noradrenaline and dopamine uptake inhibitor, indicated a surprisingly high efficacy of this drug in peripheral neuropathic pain. In conclusion, antidepressants represent useful tools in neuropathic pain treatment and must still be considered as first line treatments of neuropathic pain. However, without head-to-head comparisons between antidepressants and other analgesics, it is not possible to provide real evidence-based treatment algorithms for neuropathic pain.
Neuropathic pain is pain caused by a lesion or dysfunction in the nervous system with the primary lesion or dysfunction affecting either the peripheral or central nervous system. Prominent examples of peripheral neuropathic pain conditions are painful diabetic neuropathy, post-herpetic neuralgia and post-surgical neuropathic pain and the most common central neuropathic pain conditions are post-stroke pain, pain in multiple sclerosis and spinal cord injury pain. Neuropathic pain is also present in some other patient groups, e.g. cancer patients. Therefore, the scope of neuropathic pain is broader than the classical peripheral and central neuropathic pain conditions. The neuropathic pain conditions are most often chronic in nature and represent a real challenge in clinical practice both due to their frequency, severity and the limited number of effective treatment options.
The mainstay of pharmacological treatment of neuropathic pain is antidepressant and anticonvulsant drugs, i.e. drugs developed to be used in completely different conditions. Tricyclic antidepressants were introduced in painful diabetic neuropathy based on empiric observations about 30 years ago (Davis et al. 1977), but their potential analgesic properties were already noted shortly after their introduction more than 40 years ago (Paolo et al. 1960). The benefit of antidepressants in neuropathic pain conditions has later been demonstrated in numerous controlled trials, and there is an understanding of their mode of action in neuropathic pain from their pharmacology and the pathophysiological mechanisms of neuropathic pain. It has been shown repeatedly that antidepressants work both in patients with normal and depressed mood in a number of neuropathic pain conditions (Max et al. 1987, 1988 & 1991; Leijon & Boivie 1989; Kishore-Kumar et al. 1990), i.e. these drugs possess a genuine analgesic effect. This, of course, does not exclude that they relieve pain and depression by the same neural mechanisms.
This MiniReview will go through the pharmacology of antidepressants in relation to neuropathic pain mechanisms and present the evidence for the use of antidepressants and their efficacy in different neuropathic pain conditions. This has also been the topic of previous reviews and book chapters (McQuay et al. 1996; Sindrup 1997; Sindrup & Jensen 2001; Sindrup 2003), but our understanding of how these drugs work in neuropathic pain increases and new trials on old and new antidepressants have been published.
Pharmacology of antidepressants and pain mechanisms
- Top of page
- Pharmacology of antidepressants and pain mechanisms
- Antidepressants in neuropathic pain
The current knowledge of the pharmacological actions of tricyclic antidepressants (Baldessarini 2001) has slowly evolved through their over 40-year history. The unique ability of these drugs to inhibit the presynaptic reuptake of the monoamines serotonin and noradrenaline was elucidated many years ago as was their postsynaptic α-adrenergic, H1-histaminergic and muscarine cholinergic receptor-blocking effects. The tricyclic antidepressants have no effect on dopamine reuptake but may have some indirect dopaminergic action by the adrenergic effect and desensitization of dopamine D2 receptors. The classical tricyclic antidepressants differ in their effect on monoamine reuptake. Amitriptyline, imipramine and clomipramine cause a balanced inhibition of serotonin and noradrenaline reuptake in vivo. The serotonin reuptake inhibition is exerted by the compounds themselves whereas the noradrenaline reuptake inhibition comes from their respective metabolites nortriptyline, desipramine and desmethylclomipramine. Nortriptyline and desipramine are marketed as drugs (tricyclic antidepressants) themselves and together with the tricyclic antidepressant maprotiline, they are mainly causing inhibition of noradrenaline reuptake. These drugs have a similar action as the other tricyclic antidepressants at postsynaptic receptors and probably also act like them with respect to the other actions described below.
Binding to opioid receptors has been reported for tricyclic antidepressants, but their binding affinity is probably too low to be relevant in humans at therapeutic drug concentrations (Hall & Ögren 1981). Later evidence for an N-methyl-D-aspartate-receptor antagonist-like effect (Reynolds & Miller 1988; Cai & McCaslin 1992; McCaslin et al. 1992; Watanabe et al. 1993) which was paralleled by experimental analgesia (Eisenach & Gebhart 1995) was presented. The importance of this receptor interaction at therapeutic drug concentrations is debatable. The most recent discovery in the history of tricyclic antidepressant pharmacology is interaction with sodium channels. It has repeatedly been shown in experiments in vitro that tricyclic antidepressants block sodium channels and this effect is also seen in neuronal tissue (Ishii Y & Sumi 1992; Deffois et al. 1996; Pancrazio et al. 1998). Apparently, tricyclic antidepressants bind to the local anaesthetic receptor and cause blockade of the open and inactivated channel state at therapeutic drug concentrations (Wang et al. 2004). Tricyclic antidepressants seem also to block voltage-dependent calcium channels (Lavoie et al. 1990, Shimizu et al. 1992).
The selective serotonin reuptake inhibitors (SSRIs) are non-tricyclic drugs which are characterised by causing inhibition of serotonin reuptake without action on noradrenaline reuptake (Baldessarini 2001). This drug class is represented by fluoxetine, paroxetine, citalopram, escitalopram, sertraline and fluvoxamine. These drugs are also selective in the sense that they do not block postsynaptic receptors, or at least such actions have not yet been reported. Fluoxetine has been reported to block sodium channels, but apparently the blockade is different than the sodium channel blockade of tricyclic antidepressants (Deffois et al. 1996; Pancrazio et al. 1998). Sodium channel blockade has not been reported for the other SSRIs. There are some minor interdrug differences in pharmacology between the SSRIs, but they are probably not important.
Bupropion, another second generation non-tricyclic antidepressant antidepressant, is a noradrenaline and dopamine reuptake inhibitor without postsynaptic effects (Baldessarini 2001). Ion channel blockade has not been reported for this drug.
Serotonin noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine, milnacipran and duloxetine cause a balanced inhibition of serotonin and noradrenaline (Baldessarini 2001). These drugs are sometimes called balanced inhibitors of serotonin and noradrenaline. For venlafaxine, the balance in vivo depends on the drug dose or concentration. Venlafaxine is a serotonin and a weak noradrenaline reuptake inhibitor, but with increasing drug doses noradrenaline reuptake inhibition will increase mainly due to increasing concentrations of the metabolite R-O-desmethylvenlafaxine (Muth et al. 1991). Venlafaxine has no postsynaptic effects but it blocks sodium channels (Khalifa et al. 1999) although the characteristics of the blockade is different from that of tricyclic antidepressants. Duloxetine is itself a potent balanced inhibitor of serotonin and noradrenaline reuptake with no significant effect on a range of postsynaptic receptors or sodium channels (Wong & Bymaster 2002). The balanced monoamine reuptake inhibition has also been shown in vivo (Wong & Bymaster 2002).
The basic pharmacology of different antidepressants is summarised in table 1.
Table 1. Pharmacological profile of antidepressant drugs tried in neuropathic pain.
|Amitriptyline Imipramine Clomipramine||Nortriptyline Desipramine Maprotiline||Venlafaxine Duloxetine||Bupropion||Fluoxetine Paroxetine Citalopram|
|Ion channel blockade||Sodium||+||+||(+)/−||?||(+)/−/?|
Serotonin and noradrenaline are together with endogenous opioids and γ-aminobuturic acid neurotransmitters in the network of neurones which from centres in the brain and brainstem modulate the activity in the nociceptive pathway at the dorsal horn of the spinal cord and more rostrally in the central nervous system. Presynaptic reuptake inhibition of the monoamines serotonin and noradrenaline by antidepressants will increase the levels of these amines in the synaptic clefts and this is expected to enhance the pain suppression induced by this system. In neuropathic pain, there may be a disinhibition due to degeneration of the pain-modulating system. The degeneration could be a result of excessive stimulation of the system by excitatory amino acids released e.g. by barrages of spontaneous activity in nociceptive neurones entering the dorsal horn and by increased activity in the rest of the pain pathway.
Neuronal hyperexcitability caused by a series of signalling substances appears to play a major role in neuropathic pain. NMDA receptor-operated ion channels on second order neurones in the dorsal horn of the spinal cord represent one such family of excitatory mechanisms which render neurones hyperexcitable to stimulation. This hyperexcitability causing both spontaneous and stimulus evoked pain may be blocked by the NMDA receptor antagonist-like effect of tricyclic antidepressants, although this effect may not be fully present at therapeutic drug concentrations (see above).
In the peripheral nervous system, spontaneous activity caused by excessive expression of sodium channels may lead both to spontaneous pain and hyperexcitability. Apparently, tricyclic antidepressants have the potential to block sodium channels and thus interfere with these sodium channels in the diseased peripheral nervous system. It is now clear that sodium channels in the central nervous system are involved in neuropathic pain, since the unspecific sodium channel blocker lidocaine relieves central pain (Attal et al. 2000; Finnerup et al., 2005).
The possible calcium channel blocking effect of tricyclic antidepressants may also be important. The anticonvulsant drug gabapentin which clearly relieves neuropathic pain is now believed to act by blocking calcium channels through its binding to the α2-δ-subunit of the channel complex. Binding to the α2-δ-subunit of calcium channels reduces presynaptic release of neurotransmitters into the synaptic cleft otherwise induced by action potentials arriving at the nerve terminal. It is of course speculative if the apparent calcium channel blocking effect of tricyclic antidepressants will do the same.
It is clear that several of the actions of tricyclic antidepressants and the specific actions of the more selectively acting antidepressants have the potential to interfere with neuropathic pain mechanisms and thus relieve neuropathic pain. Fig. 1 gives an overview of the mechanisms and sites of action of tricyclic antidepressants in pain treatment.
Figure 1. Some suggested mechanisms and sites of action of tricyclic antidepressants (TCA) in neuropathic pain on peripheral nerves, in the dorsal horn of the spinal cord and at supraspinal levels. NA=noradrenaline, 5-HT=serotonin, DOPA=dopamine, NMDA=N-methyl-D-aspartate.
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- Pharmacology of antidepressants and pain mechanisms
- Antidepressants in neuropathic pain
The effect of tricyclic antidepressants in peripheral neuropathic pain is based on solid evidence with numerous trials on a range of different compounds in a number of important neuropathic pain conditions. The data on SSRIs are limited and equivocal, and under all circumstances it is indicated that their efficacy at best is moderate. The amount of data on SNRIs is increasing and suggests that drugs from this class could become a real alternative to the tricyclic antidepressants. The efficacy seems not to be quite as good as for the tricyclic antidepressants, but the SNRIs do not have any obvious contraindications and they are better tolerated. They will also be easier to use in clinical practice, since dosing according to effect and tolerability is feasible. The noradrenergic and dopaminergic drug bupropion is promising, but further studies are needed to support the current evidence obtained from only one trial.
The data on antidepressants in central neuropathic pain are limited, and it seems not to be justified to anticipate that efficacy of drugs in peripheral neuropathic pain is reflected in similar efficacy in central neuropathic pain. Although pain mechanisms may overlap between these groups, some of the basic pain mechanisms are supposed to be different. Therefore, we are at thin ice when these drugs are prescribed for disease entities belonging to this group. On the other hand, there are no other treatments with sufficient evidence at the present time. Studies have shown small treatment effects of lamotrigine in central post-stroke pain (Vestergaard et al. 2001) and of a cannabinoid in pain in multiple sclerosis (Svendsen et al. 2004). The central pain conditions are regarded to be relatively treatment-resistant. This may explain the sparse data in spite of a frequent clinical problem with e.g. central post-stroke pain experienced by as many as one in every 13 stroke sufferers (Andersen et al. 1995).
How do antidepressants work in neuropathic pain?
Enhancement of pain suppression via monoaminergic links in diffuse noxious inhibitory control induced by inhibition of presynaptic reuptake of serotonin and noradrenaline was suggested as a mechanism by which antidepressants could relieve neuropathic pain many years ago (Max et al. 1987; Sindrup et al. 1989). Taking all the present data into account, it is supposed that both of these reuptake mechanisms play a role, since tricyclic antidepressants with balanced reuptake inhibition tend to work better than noradrenergic tricyclic antidepressants and SNRIs are more efficacious than SSRIs. Further, it can be deduced that the noradrenergic mechanism appears to be most important. However, the apparent better effect of tricyclic antidepressants than of SNRIs indicates that other mechanisms contribute to the effect of tricyclic antidepressants and it is obvious to suggest the blockade of NMDA receptors and sodium channels as the candidate mechanisms. Therefore, the mechanism of action of tricyclic antidepressants in neuropathic pain is probably multimodal with contribution of monoamine reuptake inhibition and blockade of NMDA receptors and sodium channels. Bupropion provided substantial pain relief in a single study (Semenchuck et al. 2001) and this raises the possibility that a dopaminergic effect could enhance the pain-relieving effect obtained with serotonergic and noradrenergic mechanisms. This deserves further evaluation in clinical trials.
How does the efficacy compare with other treatments?
Although neuropathic pain is considered difficult to treat, several treatment options with reasonable efficacy are available at the present time. The anticonvulsant drug gabapentin has been extensively studied in peripheral neuropathic pain and relieves painful diabetic neuropathy with NNT 4.3 (2.8–8.6) and postherpetic neuralgia with NNT 4.3 (3.3–6.1) (Finnerup, personal communication). A limited amount of data shows that lamotrigine, another anticonvulsant drug, relieves peripheral neuropathic pain with NNT 4.0 (2.1–4.2) (Finnerup, personal communication). In head-to-head comparison gabapentin and amitriptyline had similar analgesic effect but the trial including 28 patients with painful diabetic neuropathy clearly was under powered to detect even clinically relevant differences in pain relief (Morello et al. 2000). The opioid drugs oxycodone and tramadol also relieved peripheral neuropathic pain; painful polyneuropathy with NNT 2.6 (1.7–6.0) and 3.5 (2.4–6.4) and postherpetic neuralgia with NNT 2.5 (1.7–5.1) and 4.8 (2.6–26.9) (Finnerup, personal communication). In postherpetic neuralgia a head-to-head comparison showed a trend of better effect of opioids than of tricyclic antidepressants (Raja et al. 2002), which contrasts the opposite rank order indicated by the NNT method. Probably there are no major differences in efficacy although higher doses of opioids could provide superior pain relief, whereas tricyclic antidepressant-dosing is probably already relatively high.
There are also data on some other drugs, e.g. other anticonvulsants and NMDA antagonists, but the evidence is limited due to either low efficacy or very limited data. Thus, in comparison with other drugs for neuropathic pain, tricyclic antidepressants are in the upper end of the efficacy range, SNRIs in the mid range and SSRIs in the lower end all as evaluated by the NNT method. Some of the other treatment options may be better tolerated at least as compared to tricyclic antidepressants, but these treatments as the antidepressants, will cause side effects in the majority of patients. The overall NNH based on drop outs due to side effects in neuropathic pain trials is 26.8 (13.7–698) for gabapentin, 23.0 (9.8–∞) for oxycodone and 9.0 (6.0–17.5) for tramadol (Finnerup, personal communication).
Combination with other treatments.
The effect of combining antidepressants with other drugs in neuropathic pain is largely unknown. Adding venlafaxine to gabapentin, if the latter provided insufficient pain relief in painful diabetic neuropathy, resulted in significant additional effect (Simpson 2001). When treatment combinations are used, it is suggested to employ combinations of drugs that do not overlap too much in pharmacological action. Thus, tricyclic antidepressants and venlafaxine could be combined with gabapentin and with opioids except tramadol which, besides the opioid effect, also interferes with the monoaminergic system. Combination of different antidepressant classes should be avoided as should be combination of any antidepressant with tramadol. In all, it must be kept in mind that combination treatments in most cases will not be evidence-based.
In conclusion, in peripheral neuropathic pain, antidepressants of the categories tricyclic antidepressants and SNRIs are fairly effective whereas SSRIs have a low efficacy. The efficacy of tricyclic antidepressants and SNRIs are either better or in the same range as other drugs used for this type of pain, i.e. gabapentin or the opioids oxycodone and tramadol. The side effects of tricyclic antidepressants, in particular the increased risk of sudden cardiac death with higher doses, may favour the choice of SNRIs or drugs from other classes. The usefulness of antidepressants in central neuropathic pain has not been finally settled.