Efficacy of pharmacological treatments of neuropathic pain: ... : PAIN (original) (raw)
1. Introduction
Neuropathic pain represents heterogenous conditions, which neither can be explained by one single aetiology nor by a particular anatomical lesion. This diversity in cause and site is reflected in entities such as peripheral nerve injuries due to trauma and poststroke pain due to ischaemic vascular lesions of the brain. Despite the different aetiology and the multiple lesions giving rise to neuropathic types of pain, many of these conditions share common clinical phenomena like: no visible injury, paradox combination of sensory loss and hyperalgesia in the painful area, paroxysms and a gradual increase of pain following repetitive stimulation (Fields, 1990; Bennett, 1994; Jensen, 1996). These observations have led to the proposal that neuropathic pain may be explained by the same or similar mechanisms. Indeed, it has been suggested that hyperexcitability peripherally and at more central sites could be a mechanism by which these pains are explained. Consequently, recent treatments have focused on drugs that reduce neuronal hyperexcitability either peripherally or centrally. For example, in peripheral nerve injuries and in postherpetic neuralgia, C-nociceptor sensitization is invoked and drugs like sodium channel blockers, which silence spontaneous and evoked activity (Devor et al., 1992) may be used. In other cases, the hyperexcitability is more amenable to blockade by drugs that reduce activity at NMDA receptors (Dray, 1997). Despite this understanding of mechanisms of hyperexcitability, treatments are not always successful. Our current knowledge has shown that hyperexcitability per se does not represent a single mechanism, but rather a combination of factors that add together and determine the degree and type of hyperexcitability in the individual patient and in a particular neuropathic condition.
One possibility to look further into mechanism is to systematically analyse drug activity in neuropathic disorders. For example by looking at efficacy of specific drugs across different disorders, it may be possible to assess whether different mechanisms are at play in different pain conditions (Woolf et al., 1998) and by looking at specific disorders across different drugs it is possible to determine whether different mechanisms are involved in specific pain conditions.
Numbers needed to treat (NNT), i.e. the number of patients needed to treat with a certain drug to obtain one with a defined degree of pain relief, has been introduced as a useful method to examine analgesic efficacy (for review see: McQuay and Moore, 1998). This method permits a clinically relevant comparison between different drugs and disorder. The purpose of this review was to evaluate efficacy by the NNT method for pharmacological treatments of neuropathic pain and compare efficacy across disorders and drugs, and if possible also across mechanisms involved.
2. Methods
The NNT (Cook and Sackett, 1995) approach has been used in recent reviews on antidepressants and anticonvulsants in neuropathic pain (McQuay et al., 1995, 1996) to give an estimate of the analgesic efficacy of these drug classes. The NNT for more than 50% of pain relieved outcome seems clinically relevant and is easily understood, and it is referred to simply as NNT in this text. It is the number of patients we need to treat with a certain drug to obtain one patient with at least 50% pain relief. More than 50% of pain relieved cannot always be evaluated directly from the data given in publications, but this goal is considered to be achieved for patients with a response characterised as ‘excellent/good/moderate’ (patient's global evaluation or pain relief), ‘no pain/slight pain’ (pain intensity) or more than 50% reduction in score (pain intensity or neuropathy scale) (McQuay et al., 1996). It is calculated as NNT=l/((goal achievedactive/totalactive)−(goal achievedplacebo/totalplacebo)) and the 95% confidence interval (CI) of NNT can be obtained by taking the reciprocal value of the 95% CI for the absolute risk reduction (Cook and Sackett, 1995).
Data on pharmacological treatments of neuropathic pain were only considered to be valid for efficacy evaluation if derived from studies performed with a randomised, placebo-controlled and double-blind design. It was decided only to include efficacy data on current and new treatments that had been tested in chronic dose settings in order to obtain NNTs that could be safely compared between drugs and conditions. Treatment given as e.g. a single intravenous infusion rarely has a place in clinical practice.
3. Results
The studies on pharmacological treatments of neuropathic pain included in this analysis are listed in Table 1. The corresponding NNTs with 95% confidence intervals and NNTs for the current treatments as reviewed previously (McQuay et al., 1995, 1996) or recalculated if necessary for specific purposes are shown for each pain condition in Table 2.
Randomised, double-blind, placebo-controlled trials of different drugs in neuropathic pain
(continued)
Numbers needed to treat to obtain one patient with more than 50% pain relief. In case of more than one study on a drug in the pertient pain type NNT is calculated for combined data. NA=Not active, ND=Not done, TCA=tricyclic antidepressants, SSRI=selective serotonin reuptake inhibitors
Tricyclic antidepressants and sodium channel blockers are currently considered to be the drug treatments of choice for neuropathic pain. There is a large number of randomised, controlled clinical trials with evidence of a beneficial effect of antidepressants in neuropathic pain, while the evidence of the sodium channel blockers is more scarce. The majority of studies have been performed in patients with postherpetic neuralgia and painful diabetic neuropathy.
3.1. Tricyclic antidepressants
From three studies in postherpetic neuralgia, the combined NNT is 2.3 (CI 1.7–3.3), from 13 diabetic neuropathy studies, NNT is 3 (2.4–4) and in one central post stroke pain study, NNT is 1.7 (1–3) (McQuay et al., l996) for antidepressants. The studies on diabetic neuropathy include trials on both tricyclics and selective serotonin reuptake inhibitors (SSRI). If studies on SSRIs are excluded together with a tricyclic tested in combination with a phenothiazine (Gomez-Perez et al., 1985), the NNT in diabetic neuropathy is 2.4 (2.0–3.0). The large number of studies in diabetic and other painful neuropathies allow an analysis of efficacy of subtypes of tricyclics. Imipramine, amitriptyline and clomipramine causes a balanced reuptake inhibition of both serotonin and noradrenaline, while desipramine and maprotiline are relative selective noradrenaline reuptake inhibitors (Hall and Ögren, 1981). In painful polyneuropathy, the combined NNT for drugs with balanced reuptake inhibition is 2.0 (1.7–2.5), while it is 3.4 (2.3–6.6) for the noradrenergic compounds. In postherpetic neuralgia, there are far fewer studies and the relationship is reversed (Table 2).
In many of the studies, the antidepressants were dosed according to effect and side effects. This may result in an underestimation of the potential effect of the tricyclics, since with these drugs, side effects are often bothersome and dose -effect or plasma drug concentration–effect relations have been found in several studies (Kvinesdal et al., 1984; Max et al., 1987; Leijon and Boivie, 1989; Sindrup et al., 1990b; McQuay et al., 1993; Kalso et al., 1995). In two studies on imipramine in diabetic neuropathy (Sindrup et al., 1990a, 1992a), the dose was adjusted to obtain the optimal plasma concentration of imipramine plus its active metabolite desipramine around 400 nM (Sindrup et al., 1990c). The target concentration was obtained in 16 of 19 patients and 5 of 18 patients, respectively. From the original data of the first study, a NNT of 1.4 (1.1–1.9) is calculated, i.e. a value below the lower 95% confidence limit for entire group of studies. This strongly indicates that the effect can be increased by this dosage policy.
The data from several of the controlled studies indicate that tricyclics are effective for both steady and lancinating or brief pains (Max et al., 1987, 1991, 1992; Sindrup et al., 1990a,b), whereas it is more difficult to judge if these drugs also relieve touch-evoked pain. It is an inherited problem with these studies that none of them addressed the issue of an effect on different pain types, but only showed that patients with the different types of pain were relieved of pain in general.
More recent data show that amitriptyline also relieves nerve injury pain quite effectively, with NNT 2.5 (1.4–2.6) (Kalso et al., 1995).
A recently reported interesting aspect of tricyclic antidepressants in pain treatment is the apparent potential to reduce the risk of developing postherpetic neuralgia by low dose amitriptyline during the acute phase of herpes zoster (Bowsher, 1997).
3.2. Selective antidepressants
The selective serotonin reuptake inhibitors (SSRI) is a new class of antidepressants. They differ from classical tricyclic antidepressants in their specific inhibition of presynaptic reuptake of serotonin but not of noradrenaline and their lack of the postsynaptic receptor blocking effects and quinidine-like membrane stabilization seen with the tricyclics. In two out of three studies on SSRIs in painful diabetic neuropathy, there was a significantly better effect of the SSRI than of placebo (Sindrup et al., 1990a, 1992b; Max et al., 1992) (Table 1). The individual NNT from the studies showing a significant effect is 2.9 (paroxetine) and 7.7 (citalopram) and the combined NNT for all three studies is 6.7 (3.4–435). Paroxetine seems to relieve both steady and lancinating pain (Sindrup et al., 1990a). Central pain is not relieved by citalopram (Vestergaard et al., 1996).
The results from these and other studies in diabetic neuropathy indicated that drugs with a balanced inhibition of serotonin and noradrenaline but without the postsynaptic and quinidine-like effects of the TCAs could be as effective as the tricyclics (Sindrup, 1994) and at the same time be better tolerated. One such drug, venlafaxine, has been marketed for the treatment of depression. Preliminary data from a randomised, double-blind, placebo-controlled study on venlafaxine in neuropathic pain following treatment of breast cancer indicate that venlafaxine has some effect but data for calculation of NNT are not available (Tasmuth and Kalso, 1998).
3.3. Ion channel blockers
Lidocaine is the prototype of an unspecific sodium channel blocker. More than 10 years ago, it was reported that infusions of lidocaine relieved painful diabetic neuropathy (Kastrup et al., 1987) and the data from that study show a favourable NNT of 3 (5–10). Lidocaine is not convenient for chronic treatment, since it cannot be dosed orally. Studies on its oral analogue mexiletine have therefore been carried out. Two of the studies found a better effect of mexiletine than of placebo (Dejgard et al., 1988; Oskarsson et al., 1997) while the two other studies either reported no effect (Wright et al., 1997) or only effect in sub-analyses and not on primary effect variables (Stracke et al., 1992) (Table 1). Dichotomous data are reported in one of the studies favouring mexiletine (Oskarsson et al., 1997), but it is important to mention that only the highest of three dose levels tested in that study was better than placebo. The NNT for this dose level (675 mg/day) is 10 (3.0–∞). Data on the effect on different pain categories are not available.
One trial studied the effect of mexiletine in chronic dysaesthethic pain after spinal cord injury but failed to find an effect (Chiou-Tan et al., 1996).
Phenytoin and carbamazepine are widely used as anticonvulsants. These drugs exert their membrane-stabilizing properties by blocking sodium channels unspecifically (Dray, 1997) and therefore reduce neuronal excitability in sensitized C-nociceptors. In painful diabetic neuropathy, carbamazepine has an NNT of 3.3 (2–9.4) and phenytoin an NNT of 2.1 (1.5–3.6) (McQuay et al., 1995). There is only one trial on each drug (Rull et al., 1969;Chadda and Mathur, 1978) and it is important that a second placebo-controlled study with phenytoin failed to demonstrate a significant effect of this drug (Saudek et al., 1977). The carbamazepine dose used (titration from 200 to 600 mg/day) is rather low and it is possible that the efficacy could be increased by using higher doses. Although carbamazepine is frequently used in post-stroke pain, it is not significantly better than placebo in the small study (n=14) that showed a clear effect of the tricyclic antidepressant amitriptyline in this condition (Leijon and Boivie, 1989). However, the corresponding NNT of 3.4 (1.7–105) is quite acceptable and the lack of statistical significance may simply be related to the small sample size.
Carbamazepine is the treatment of choice for trigeminal neuralgia and data from three controlled trials have been published (Campbell et al., 1966; Killian and Fromm, 1968; Nicol, 1969). It is difficult to interpret the data from the latter study, which also failed to find an effect. For the two other studies, there is a combined NNT of 2.6 (2.2–3.3) (McQuay et al., 1995). It is reported that carbamazepine both causes a reduction in pain intensity, a reduction in pain paroxysms and in triggers (Campbell et al., 1966). There are only anecdotal data on oxcarbamazepine (Zakrzewska and Patsalos, 1989), a new carbamazepine-like anticonvulsant acting by sodium channel blockade and characterized by a less bothersome side effect profile than carbamazepine.
Lamotrigine is a new anticonvulsant, which acts by stabilising the slow inactivated conformation of a subtype of sodium channels and probably by this mechanism suppress the neuronal release of glutamate. Anecdotal observations in patients with central pain (Canavero and Bonicalzi, 1996) and an uncontrolled study in painful diabetic neuropathy (Eisenberg et al., 1998) indicate that lamotrigine will in fact relieve neuropathic pain. Lamotrigine has been tried as add on treatment to carbamazepine in trigeminal neuralgia (Zakrzewska et al., 1997), and in this setting it has a favourable NNT of 2.1 (1.3–6.1).
In the studies on diabetic neuropathy and central pain, there are no data on the types of pain that respond to the sodium channel blockers, but the efficacy of several of these drugs in trigeminal neuralgia (Campbell et al., 1966; Killian and Fromm, 1968; Zakrzewska et al., 1997) strongly indicate an effect on lancinating pains and pain paroxysms.
Gabapentin is a novel anticonvulsant with an unknown mechanism of action. It does not interact with GABA receptors or GABA metabolism and it has no effect on sodium channels. Recent data suggest that it blocks a subtype of calcium channels on neurones. After several uncontrolled studies (e.g. Rosenberg et al., 1997) with gabapentin in neuropathiuc pain, the first two controlled studies have recently been presented (Table 1). In an adequately designed study with 165 patients with painful diabetic neuropathy, gabapentin in a dose of 3600 mg/day was compared to placebo and the NNT was 3.7 (2.4–8.3) (Backonja et al., 1998). There are no data on the effect on individual pain types in that study. Data from a placebo-controlled study in postherpetic neuralgia show a NNT value of 3.2 (2.4–5.0) (Rowbotham et al., 1998).
3.4. GABA-B receptor agonist
Baclofen is a GABA-B receptor agonist, which has been examined in trigeminal neuralgia (Fromm et al., 1984;Fromm and Terrence, 1987). These authors demonstrated a significant pain-relieving effect of baclofen and the NNT for a significant decrease in painful paroxysms was 1.4 (1.0–2.6) and later showed that the L-baclofen is more effective than racemic baclofen.
3.5. NMDA antagonists
The evidence of involvement of excitatory amino acids in neuropathic pain has also prompted studies on drugs with an NMDA-antagonistic effect. One such drug is ketamine and intravenous infusion studies with a double-blind, placebo-controlled design have shown an immediate effect of ketamine in patients with chronic neuropathic pain (Max et al., 1995; Felsby et al., 1996). Ketamine orally for a few months has been tried in single patients with neuropathic pain and the results are rewarding (Broadley et al., 1996; Nikolajsen et al., 1997), but controlled trials on oral ketamine in neuropathic pain have not been published.
The low affinity NMDA channel blocker dextromethorphan relieved diabetic neuropathy with NNT 1.9 (1.1–3.7), whereas it had no effect in postherpetic neuralgia (Nelson et al., 1997). It was reported that in diabetic patients, there was no difference between good and poor responders with respect to pain quality.
A preceding study on dextromethorphan included both patients with central post-stroke pain and different types of neuropathic pain of peripheral origin (McQuay et al., 1994). This study used a much lower dose than the above study and no effect of dextromethorphan was found. A similar lack of effect was also seen in 9 patients with post-stroke pain, which was the largest patient subgroup.
In a recent study on the non-competitive NMDA receptor antagonist memantine it was reported that it did not relieve postherpetic neuralgia (Eisenberg et al., 1998).
3.6. Opioids
Following the dispute 10 years ago on opioid sensitivity of neuropathic pain (Arner and Meyerson, 1988; Portenoy et al., 1990; McQuay et al., 1992), there is now less controversy whether opioid analgesics are of any benefit in neuropathic pain. Evidence is now compiling that opioids are effective in certain types of neuropathic pain. Intravenous infusion of morphine relieves postherpetic neuralgia (Rowbotham et al., 1991), and it was recently shown that infusion of fentanyl, which is also a μ-opioid receptor agonist, relieves different types of neuropathic pain states (Dellemijn and Vanneste, 1997). The effect of the μ-opioid receptor against oxycodone has been tested in postherpetic neuralgia in a long-term trial with oral dosing (Watson and Babul, 1998) (Table 1). Oxycodone was superior to placebo, but in 30% of the patients oxycodone was used as an add on drug to treatment with antidepressants. The calculated NNT of 2.5 (1.6–5.1) for oxycodone has therefore to be judged with caution. It was clearly shown that oxycodone relieves both steady pain, brief pain and allodynia and 67% of the patients preferred oxycodone as compared to 11% preferring placebo.
Tramadol is an analgesic drug, which probably acts through both monoaminergic and opioid mechanisms. The monoaminergic effect is shared with the tricyclic antidepressants. Further, development of tolerance and dependence during long-term tramadol treatment appears to be uncommon and tramadol seems to have a low abuse liability. Therefore, tramadol may be an alternative to strong opioids, and two recent studies tested the drug in painful diabetic polyneuropathy (Harati et al., 1998) and painful polyneuropathy of different etiologies (Sindrup et al., 1998). Tramadol was superior to placebo in both studies and came up with NNTs of 3.1 and 4.3, and the combined NNT was 3.4 (2.3–6.4). In the latter study, nearly 80% preferred tramadol for placebo and it was shown that tramadol parallel with its relief of on-going pain reduced touch-evoked pain and experimentally induced mechanical allodynia.
3.7. Levodopa
Dopamine agonists inhibit noxious input to the spinal cord (Jensen and Yaksh, 1984). Levodopa, being a dopamine precursor, may have a similar effect or may act as a precusor to noradrenaline and modulate pain via noradrenergic mechanisms. Nearly 20 years ago, it was found in an adequately designed study that levodopa reduced pain in acute herpes zoster (Kembaum and Hauchecome, 1981) and recent data show that this is also the case in diabetic neuropathy (Ertas et al., 1998). In diabetic neuropathy, NNT was 3.4 (1.5–∞) and the study did not differentiate the type of pain that responded to the treatment.
3.8. Capsaicin
Capsaicin, an alkaloid derived from chillies, depletes the neurotransmitter substance P from sensory nerves.
Topically applied capsaicin cream showed a significant effect in 3 of 5 studies in diabetic neuropathy (Chad et al., 1990; Scheffler et al., 1991; Capsaicin Study Group, 1991; Tandan et al., 1992; Low et al., 1995) with NNTs in the positive studies from 2.5 to 4.9 and a combined NNT for all studies of 5.9 (3.8–13).
Capsaicin has been tried with a positive outcome in postherpetic neuralgia (Bernstein et al., 1989) and pain after nerve injury (Watson and Evans, 1992) and the NNTs are 5.3 and 3.5, respectively.
Although this treatment may have few side effects besides the burning pain on application at treatment start, it may be less convenient in many patients, since it has to be applied 4 times daily on the entire painful area.
4. Discussion
The present review indicates that NNT to determine treatment efficacy in neuropathic pain provides consistent values for different drug classes. In painful diabetic neuropathy, the most extensively studied pathological condition, NNT values for tricyclic antidepressants and sodium channel blockers are around 2–3. This means that in neuropathic pain, 2–3 patients have to be treated before one patient with ≥50% pain relief is obtained. The benefits and limitations of this simple approach will be discussed briefly in the following (see Fig. 1).
Numbers needed to treat (NNT) to obtain one patient with more than 50% pain relief for different drugs in different neuropathic pain conditions. NNT is shown in two directions to enable comparison between different drugs in the same condition and across different conditions for the same drug or drug classes. Symbol placed in the upper right hand corner of a box indicates that the drug is inactive in the pertinent pain condition or has a NNT=10 (confer Table 2). TCA=tricyclic antidepressants, SSRI=selective serotonin reuptake inhibitors, PHEN=phenytoin, CARB=carbamazepine, GABA=gabapentin, LAMO=lamotrigine, MEX=mexiletine, DEXTRO=dextromethorphan, MEMA=memantine, OXY=oxycodone, TRAM=tramadol, L-DOPA=levodopa with benzerazide, CAPS=capsaicin, BACLO=baclofen.
4.1. Outcome measures
A major problem in many clinical drug trials is the failure to predict outcome because individual trials often include a small sample size. In a recent study (Moore et al., 1998), it was shown that it is only possible to determine efficacy of a treatment from large trials. Thus, a meta-analysis of several trials may be necessary to generate a sufficient number of patients to determine the usefulness of a specific drug. With the use of a common outcome measure such as NNT-values, it is possible to compare and combine several studies. For pain, an essential parameter is obviously the degree of pain relief associated with a particular drug. From available studies, it is not always possible to determine a 50% pain relief and accordingly this gives rise to some uncertainty. However, it has been argued that since NNT describes the difference between treatment and control, a changing threshold for calculating NNT does not affect the result much (McQuay and Moore, 1998). An almost equally important aspect in determining drug efficacy is the potential harmfulness associated with a particular drug. In a final analysis of a drug, it may therefore be essential also to determine the numbers needed to harm (NNH), i.e. the numbers needed to treat before there is one patient with pronounced or intolerable side effects. Future studies in which quantitation of pain relief and harmful side effects are decided a priori may be important in determining the degree of uncertainty associated with such retrospective outcome measures.
4.2. New versus established treatments
The calculated NNT for tricyclic antidepressants in painful polyneuropathy are based on a sufficient total number of patients to make an accurate estimate. On the other hand, the NNT for tricyclics in other neuropathic pain conditions, the NNTs for carbamazepine and phenytoin as well as for the more recent treatments are all calculated from a relatively small number of patients. For these treatments, the NNT may be considered indicative of their potential effect in the pertinent pain condition. In painful polyneuropathy, selective serotonin reuptake inhibitors, mexiletine and capsaicin, are clearly less effective than the established treatment, whereas gabapentin, tramadol, dextromethorphan and Symbol-dopa appear to be equally effective with the older treatments. The new treatments are generally better tolerated and therefore the equally effective of them may be considered superior to the established treatments and even the less effective may be useful in situations where other treatments cannot be used. Among the new drug types, dextromethorphan has the most favourable NNT, but it still is not superior to optimally dosed tricyclics.
In the other pain conditions, tricyclic antidepressants also seem to be superior with respect to effect, although oxycodone is equally effective in postherpetic neuralgia and in trigeminal neuralgia carbamazepine and lamotrigine are the only treatments that have been tested in adequately designed trials.
4.3. NNT values for specific pain conditions
In the present review, it is seen that for diabetic neuropathy, an NNT value between 2–4 is obtained for the tricyclic antidepressants, the sodium channel blockers phenytoin and carbamazepine, the dopamine precusor L-dopa, the weak opioid tramadol and for gabapentin, whereas selective serotonin reuptake inhibitors and mexiletine are either ineffective or have substantially higher NNT values. Tricyclics are known to exert a multitude of actions such as a monoamine reuptake inhibition (Hall and Ogren, 1981), sodium and calcium channel blockade (Lavoie et al., 1990; Pancrazio et al., 1998), an antihistaminergic action (Taylor and Richelson, 1980) and a weak NMDA receptor-blocking action (Reynolds and Miller, 1988). Carbamazepine, on the other hand, exerts probably solely a sodium channel-blocking effect, yet both drugs have almost similar NNT value. The reason for this similarity in NNT between drugs despite differences in mechanism of action is not clear. It is possible that the NNT value is in fact a sufficient measure to predict outcome regardless of the differential mechanisms of action of these drugs. Alternatively, the NNT value may be an inaccurate measure for separating different drugs on a specific pathological pain condition. One way to optimise the sensitivity of NNT to detect differences between drugs must be to calculate it separately for different aspects of pain (steady pain, pain paroxysms, touch-evoked pain etc.), which is not possible from the available studies. The observation that many different drug classes have similar NNT in a pain condition supports the notion that other factors than underlying pathological mechanism dictate treatment response, since these drugs all have different mechanisms of action.
The present data analysis shows that treatment efficacy with tricyclic antidepressants depends on the dosage policy. Thus, by optimising the dose according to plasma drug concentrations, the NNT in painful polyneuropathy could be reduced significantly. Some of the NNT values obtained in studies with dosing according to effect and side effects may primarily reflect the tolerability of the drugs instead of their potential efficacy. This may explain why studies with dosing according to effect and side effects fail to find a difference in efficacy between tricyclics with both serotonin and noradrenaline reuptake inhibition and tricyclics with relatively selective inhibition of noradrenaline reuptake (Max et al., 1992), while this is found when fixed doses are used (Sindrup et al., 1990b; Vrethem et al., 1997). It could also be the reason for the finding that in postherpetic neuralgia there is a reversed relation between the efficacy of these subgroups of tricyclics (Table 2).
For many drugs, the optimal dose interval is not known and a comparison of the NNT values is only meaningful if it can be related to the corresponding NNH (H.J. McQuay, personal communication). In this respect, it is of interest to note that the sodium channel blocker mexiletine has a higher NNT in painful diabetic neuropathy than the other sodium channel blockers carbamazepine and phenytoin. This may reflect a less effective drug or a side effect profile that does not allow optimal dosing with respect to efficacy. A more appropriate measure for clinical purposes in the future may be one that uses the ratio of NNT and NNH. Drugs with a low NNT/NNH ratio will generally be superior to drugs with a high NNT/NNH ratio.
4.4. NNT values for specific drugs
As also seen from the present survey, when looking at individual drug groups, the NNT value for TCAs is almost identical across different painful conditions such as postherpetic neuralgia, painful polyneuropathy and peripheral nerve injury pain. Again, from available data, it is not possible to determine whether this apparent failure to distinguish between pain conditions on the basis of NNT reflects an insufficiency in the NNT measure to detect differences between conditions. In the listed conditions, a combination of phenomena including allodynia, paroxysms and sympathetic dysfunction may be present and probably in different degrees. While the pathology from one condition to another may differ, the combination of phenomena seen in one group of patients may not necessarily differ from that seen in another group. So, in these cases, identical NNT may be seen even if different pathologies are involved. It is possible that introduction of more sensitive scales to monitor effect can ‘dissect’ the various phenomena and clarify the contribution of different phenomena to a global effect.
However, some differences within drug class between different pain conditions are observed. Dextromethorphan relieves painful diabetic neuropathy, but not postherpetic neuralgia and central post-stroke pain, and SSRIs relieve diabetic neuropathy slightly but have no effect on post-stroke pain. This may reflect differences in pain mechanism, but also differences in sensitivity of the trial and maybe the severity of pain in the pertinent pain condition.
4.5. Current classification of neuropathic pain
Neuropathic types of pain are heterogenous in terms of underlying pathology and anatomical site in the nervous system. They do have a common core of essential phenomena, which are met by many neuropathic patients and seen in various combinations depending on the particular type of neuropathic pain. So far, neuropathic pains have been classified according to the type of underlying pathology, e.g. diabetes, herpes zoster or stroke, or into peripheral versus central lesions. However, this distinction does not take into account the possible mechanisms that may be present, e.g. touch-evoked allodynia due to A-beta fiber recruited central sensitisation, C-fiber mechanosensitivity and sympathetic hyperactivity. Experimental and recent small clinical trials have shown that touch-evoked pain or pain responses can be reduced by NMDA receptor antagonists with known action on central hyperexcitability (Dray et al., 1994; Eide et al., 1994; Felsby et al., 1996). Hyperalgesic phenomena can also be reduced by sodium channel blockers like lidocaine. At present, there are no data available to show whether such an approach can be applied to patients with different neuropathic pain conditions. Animal studies on experimental painful neuropathy in which a single neuropathic phenomenon like touch-evoked avoidance behaviour or paw withdrawal threshold to graded von Frey hairs are recorded have permitted separation of drugs with an action mainly on allodynia-like pain or on pin prick hyperalgesia (for review see:Yaksh, 1997). It is to be noted, however, that the simple and often single abnormality recorded in behavioral animal studies (e.g. paw-withdrawal to von Frey hair stimulation) rarely are matched by a similar simple picture in the clinic. An extensive examination of the various phenomena encountered in neuropathic patients with specific conditions, and how these are modified by drugs, will in the future tell us whether a mechanism-based classification can be applied to NNT. Such an approach may also be useful if combination of treatments are used.
5. Conclusion and perspectives
Despite the increasing number of trials of different drugs in different neuropathic pain conditions, it is still only the efficacy of tricyclic antidepressants in painful polyneuropathy and postherpetic neuralgia that relies on a sufficiently large total number of patients studied. Some of the studies on the new treatments, such as tramadol in painful polyneuropathy, and gabapentin in painful polyneuropathy and postherpetic neuralgia may rely on an adequate number of patients, but they are based on only one or two trials. None of the new treatments appear to be more effective than the tricyclics or the older anticonvulsants, and optimal dosing of the tricyclics may improve the efficacy of these drugs. However, the new treatments may represent a progress due to their supposed better tolerability. The NNT measure of efficacy did not reveal any large or consistent differences in effect across different pain conditions for each drug class or by different drug classes in single pain condition. Establishment of NNT and NNH values for each type of drug and for various pain conditions will be a useful clinical guide. Future studies on the effect of different drugs on different neuropathic pain phenomena may unmask pain mechanisms and guide choice of treatment for single patients. In this respect it may be useful to develop new scales that permit a quantification of different phenomena. Pre-emptive treatment with e.g. tricyclic antidepressants may be a new research direction.
Acknowledgements
This study was supported by a grant from the Danish Medical Research Council (Grant no. 42820). We would like to thank Dr. H.J. McQuay for helpful comments on an earlier draft version of this paper.
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Keywords:
Pharmacological treatments; Neuropathic pain; Placebo-controlled trials
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