Classical Anti-depressants

16 May

The anti-nociceptive effects of anti-depressants require intact descending in- hibitory bulbospinal pathways. A study by Ardid (1995) shows that the anti- nociceptive effects of clomipramine are suppressed only in the hindpaw ipsi- lateral to a unilateral lesion of the dorsolateral funiculus of the rat (Ardid et al.

1995). The effects of clomipramine, amitriptyline and desipramine were tested on a neuropathic  pain model in rats induced by loosely tied ligatures around

the common  sciatic nerve. Acute injections of clomipramine,  amitriptyline and desipramine  caused pain relief. Chronic injections of these three TCAs

resulted in pain relief as measured by a significant and progressive increase in vocalization threshold.

Sierralta et al. (1995) use p-chlorophenylalanine and α-methyltyrosine  to

examine the anti-depressant drugs clomipramine, zimelidine, imipramine and

maprotiline  in the acetic acid writhing  test in mice. Each anti-depressant demonstrated an anti-nociceptive  effect in this study. This study shows that critical levels of both 5-HT and NA are responsible  for mediating  the anti- nociceptive effects of anti-depressants on the writhing test in mice (Sierralta et al. 1995).

The streptozocin-induced diabetic rat is a model of chronic pain with signs of hyperalgesia and allodynia. The TCAs clomipramine,  amitriptyline  and desipramine,  as well as clonidine, an α-adrenergic  stimulating  agent, were studied in this pain model to show that noradrenergic  drugs seem to be the

most active of these drugs that act on monoaminergic  transmission  to cause pain relief (Courteix et al. 1994).

Fishbain et al. (2000) conducted  a review of 22 controlled animal studies and 5 double-blind placebo-controlled studies that examined anti-depressants in various pain models. This group found that anti-depressants that atten- uate both serotonin  and norepinephrine levels have greater anti-nociceptive

activity than anti-depressants that solely act to modulate the NA levels. Fur- thermore,  anti-depressants that act solely to modulate  serotonin  levels have weaker anti-nociceptive properties than the two previously mentioned classes of anti-depressants (Fishbain et al. 2000). Bomholt (2005) in a study of various anti-depressants in the chronic constriction  injury rat model of neuropathic pain suggests that anti-depressant drugs that act on both serotonin  and NA levels have greater anti-nociceptive  effects than SSRIs (Bomholt et al. 2005). The anti-depressants amitriptyline,  duloxetine, mirtazapine  and citalopram were able to attenuate thermal hyperalgesia in the chronic constriction injury rat model of neuropathic  pain. Interestingly, only amitriptyline,  a TCA, and duloxetine, a dual serotonin-norepinephrine reuptake inhibitor, fully reversed thermal hypersensitivity. Amitriptyline, duloxetine and mirtazapine,  a nora- drenergic and specific serotoninergic  anti-depressant (NaSSA) caused a sig- nificant reduction  of mechanical hyperalgesia, whereas citalopram, an SSRI, was ineffective in attenuating  mechanical hyperalgesia. Mechanical allodynia was not affected by any of these four anti-depressants (Bomholt et al. 2005).

Which receptors underlie the effects of the increased levels of monoamines in synapses as a result of their primary action on uptake mechanisms? Mico (1997) provides supporting  evidence that β-adrenoceptors  play a role in the analgesic effect of desipramine and nortriptyline. However, only the β1 adren- ergic receptor is involved when the painful stimulus is chemical, as tested by the non-neuropathic acetic acid and formalin tests (Mico et al. 1997). However, these are not neuropathic states, and further studies that show α-adrenoceptors play a role  in  the  physiology of pain  transmission.  Anti-depressant  anti- nociception is mediated by α2-adrenoceptors,  and not α1-adrenoceptors,  and not only by drugs that act by re-uptake inhibition of NA, but also of serotonin (Gray et al. 1999).

As seen in the treatment of diabetic neuropathy, the TCA imipramine has an NNT of 1.4 in a study with optimal doses. Other studies of tricyclics show an NNT of 2.4 in this pain disorder. Furthermore,  SSRIs have an NNT of 6.7. The NNT is 3.3 for CBZ, 10.0 for mexiletine, 3.7 for GBP, 1.9 for dextromethorphan,

3.4 for both tramadol and levodopa, and 5.9 for capsaicin (Sindrup et al. 1999). In diabetic neuropathy,  the NNT for anti-depressants was 3.4 and the NNT

for anti-convulsants  was 2.7 (Collins et al. 2000). Anti-depressants  and anti- convulsants had the same efficacy and incidence of minor adverse effects in for diabetic neuropathy  and PHN (Collins et al. 2000) In PHN, TCAs have an

NNT of 2.3. The NNT for PHN is 3.2 for GBP, 2.5 for oxycodone and 5.3 for capsaicin. Dextromethorphan was inactive in PHN (Sindrup  et al. 1999). In PHN, the NNT for anti-depressants was 2.1 and the NNT for anti-convulsants was 3.2 (Collins et al. 2000). The NNT was 2.5 for tricyclics and 3.5 for capsaicin

in peripheral nerve injury (Sindrup et al. 1999).

In the treatment of pain in polyneuropathy, TCAs and anti-convulsants have become the conventional pharmacotherapy. According to the study by Sindrup and Jensen (2000) TCAs are the drugs of choice in the pharmacological treat-

ment of pain in polyneuropathy. GBP, CBZ, and tramadol are good alternatives to TCAs if contraindications or tolerability problems  are encountered  with this class of drugs. Sindrup et al. (1999) found no obvious relationship  be- tween the mechanism of action of these drugs and their effect in distinct pain conditions or for specific drug classes and various pain conditions (Sindrup et al. 1999). McQuay et al. (1996) reviewed 21 placebo-controlled  treatments including data on 10 different anti-depressants in 17 randomized  controlled trials. An NNT of 3 for anti-depressants when compared with placebo shows significant pain relief in the 6 of 13 studies of diabetic neuropathy. PHN studies have an NNT of 2.3. The odds ratio for anti-depressants from two atypical facial pain studies is 4.1 and the NNT is 2.8. From the only central pain study with analysable dichotomous  data, the NNT for anti-depressants was estimated to be 1.7 (McQuay et al. 1996).

However, since the early anti-depressants have a number of potential phar- macological targets,  there  may be non-monoamine actions  of these  com- pounds,  although it is unclear that they contribute  to the clinical effects of these compounds.  Skolnick et al. (1996) examined the effect of chronic anti- depressant  treatment  on NMDA receptors. Adaptive changes in radioligand binding to NMDA receptors  resulted from chronic (14 days), but not acute (1 day), anti-depressant administration to mice. The TCA imipramine,  the SSRI citalopram, and electroconvulsive shock slowly produce these adaptive changes that persist for some time after treatment  has been stopped. How- ever, the ability of SSRIs, weakly effective in patients, to produce these actions, seemingly limited to the cerebral cortex, argue against a contribution to the clinical actions of anti-depressants in pain.

Valverde et al. (1994) have shown that  anti-nociception associated  with TCAs acts partly via the endogenous opioid system and partly by additional activation of noradrenergic and serotonergic pathways, although this study did not address nerve injury. De Felipe et al. (1985) found that rats treated chron- ically for 21 consecutive days with the typical anti-depressants clomipramine, desipramine  and amitriptyline,  as well as with the atypical anti-depressants iprindole and nomifensine, had increased levels of [Met5]enkephalin in stria- tum and nucleus accumbens.

Hamon et al. (1987) examined the central mechanisms  involved in anti- depressant  potentiation of morphine-induced analgesia. Levels of Leu-enke- phalin, the opioid peptide, are markedly increased in the spinal cord, hypotha- lamus and cerebral cortex after a 14-day chronic treatment  of amoxapine or amitriptyline. Met-enkephalin levels were increased after amitriptyline treat- ment in the spinal cord and hypothalamus.  Chronic treatment  with amoxap-

ine or amitriptyline  caused an increase of δ- and μ-opioid binding  sites in the spinal cord and decreased in the hypothalamus; opioid receptor levels re-

mained unchanged in the cerebral cortex (Hamon et al. 1987). However, due to the close relations between monoamine systems and opioids in the brainstem

and midbrain, these secondary effects on opioid function are not unexpected.

Indeed, the anti-nociceptive  properties  of clomipramine  and amitriptyline, as well as their ability to potentiate  morphine-induced analgesia, seem to be linked to the activation of a serotonin-mediated endogenous  opioid system. Sacerdote et al. (1987) have shown that acute administration of clomipramine and amitriptyline  (acting on NA and 5HT), induce analgesia. Nortriptyline, a TCA that acts predominantly via the noradrenergic  system, does not induce analgesia when administered  acutely. However, acute dosing of nortriptyline, amitriptyline  and clomipramine  all potentiate  the anti-nociceptive  effects of morphine, which further exemplifies a relationship between the serotoninergic and the endogenous opioid systems (Sacerdote et al. 1987). Here as in many studies, the relation of effects seen with acute doses to the clinical profile of drugs used for chronic treatments is unclear.

Using a rat model of neuropathic  pain, caffeine blocks the thermal  anti- hyperalgesic effect of acute amitriptyline in a rat model of neuropathic  pain. Concurrent systemic administration of both caffeine and amitriptyline blocked amitriptyline thermal anti-hyperalgesic effect. No observable effects inherent to caffeine were found at this dose. Spinally, the mild anti-hyperalgesic effect of amitriptyline was unchanged by pretreatment with intrathecal caffeine. Using brief anaesthesia, peripherally administered amitriptyline into the neuropathic paw resulted in anti-hyperalgesia. Furthermore, anti-hyperalgesia due to both doses of amitriptyline  were partially antagonized  with co-administration of caffeine. Ultimately, this study suggests that acute amitriptyline’s thermal anti- hyperalgesic effects in this model may involve increase of a peripheral endoge- nous adenosine  tone (Esser and Sawynok 2000). In a randomized,  double- blind, placebo-controlled  study of 200 adult patients, topically administered

3.3% doxepin hydrochloride, 0.025% capsaicin and a combination of 3.3% dox- epin/0.025% capsaicin were found to provide similar levels of anti-nociception

in human chronic neuropathic pain. However, a more rapid onset of analgesia was produced by the combination of doxepin/capsaicin (McCleane 2000).

In line with peripheral  actions under some conditions, Abdi et al. (1998)

examined  the acute effects of amitriptyline  and GBP on behavioural  signs of mechanical allodynia using the Chung rat model of neuropathic  pain. In a second experiment,  continuous  discharges in fascicles of injured  afferent fibres were recorded. Amitriptyline and GBP increased the mechanical allody- nia threshold and amitriptyline depressed the rate of continuing discharges of injured afferent fibres, whereas GBP had no effect on these discharges. Neuro- pathic pain behaviour in rats is clearly modulated by both amitriptyline and GBP. The site of action of GBP is exclusively central; amitriptyline appears to act both peripherally and centrally (Abdi et al. 1998), but with regard to the former, little is known whether this potential action acts on evoked responses or contributes to the effects seen in patients after systemic doses.

It is known that amitriptyline, as well as other anti-depressants, has a high binding affinity for NMDA receptors in vitro. Intrathecal  amitriptyline  com-

pletely antagonized  thermal  hyperalgesia induced by NMDA. Some authors

have suggested that  TCAs intrathecally  administered  may provide  greater pain relief than systemically administered  TCAs, which are known to provide modest activity in the treatment  of clinical neuropathic  pain. Inflammation- induced thermal hyperalgesia was reversed by intrathecal  amitriptyline. The anti-nociceptive  effect of amitriptyline  was unaffected, except at the lowest dose, by block of NA and 5HT receptors. Hyperalgesia is reversed by amitripty- line in rats by a mechanism not linked to monoamine reuptake inhibition, and possibly due to NMDA receptor antagonism (Eisenach and Gebhart 1995).

However, these animal studies, often using thermal tests and acute doses, need to be expanded to include studies on allodynias and ongoing pain after

nerve injury  to better  replicate  the clinical situation.  They also fail to ex- plain why, if the effects of the TCAs are peripheral  and/or  central and not mediated by monoamines,  sedation and cardiovascular effects, hallmarks of

noradrenergic  activity, are so common in patients. A significantly higher rate of serious adverse cardiac events occurs during nortriptyline  treatment  than during treatment with paroxetine (Roose et al. 1998).

Venlafaxine, a serotonin  and noradrenergic  reuptake inhibitor  (SnaRI), is effective in multiple pain disorders  and has an improved  side-effect profile when compared to TCAs (Mattia et al. 2002).

Schreiber et al. (1999) have shown that the κ- and δ-opioid receptor subtypes

strongly influenced  the anti-nociceptive  effect of venlafaxine, with the α2- adrenergic  receptor  also contributing  to the anti-nociceptive  effect of this drug (Schreiber et al. 1999). α2- and a minor α1-adrenergic mechanisms of

anti-nociception are implicated by tests where adrenergic and serotoninergic antagonists  were used; venlafaxine-induced  anti-nociception was decreased by yohimbine but not phentolamine  or metergoline. Furthermore,  clonidine,

an α2-adrenergic agonist, significantly potentiated venlafaxine-mediated anti- nociception (Schreiber et al. 1999).

Conclusion

As has been pointed out in this account, there are multiple mechanisms of neu- ropathic and other pains, and in the case of the many peripheral neuropathies, changes can be charted from the periphery, through the spinal cord and into the brain. Thus, the fact that both anti-depressants and anti-convulsants, with very different mechanisms, can be effective is not surprising since they target key but parallel systems involved in this pain state. A better understanding of the multiple mechanisms of neuropathic  pain should lead to a more effective use of existing drugs, possibly allowing a greater number of patients to benefit, and provide a basis for the development of potential new therapies.

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