Search methods, ranking criteria, and statistical analysis
1. Painful neuropathy
In patients with painful neuropathy, how do drug treatments affect the probability of reducing pain? What is the probability of adverse effects?
PPN is the neuropathic pain condition that has been most intensively studied in controlled trials (a total of 3567 patients in our analysis) (Table 7.1).
Tricyclic antidepressants
Eleven small cross-over, class-I or II RCTs, dating from 1984 to 2003, have established the efficacy of Tricyclic antidepres-sants (TCA) (amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, and the tetracyclic maprotiline) in PPN [19,27]. TCA in PPN was significantly better than placebo (P 0.0001), with a combined Reliability over 11 trials of 77 and Net Gain of 38%. The TCA most effective is nortriptyline 30 mg, scoring 84% gain; amitriptyline (pro-bably the most used in clinical practice) provides on average a 41% Net Gain. There were only two head-to-head trials (both Class I). In one, clomipramine and desipramine were not significantly different [31]. In the other amitriptyline was slightly but significantly more effective than maprotiline [39]. The most common side effects of TCA are dry mouth, constipation, sweating, dizziness, disturbed vision, drowsi-ness, palpitation, orthostatic hypotension, sedation, and urin-ary hesitation. More selective TCAs such as nortriptyline are better tolerated than the non-selective TCA, with less anti-cholinergic effects and sedation [40]. A suspected associa-tion between TCA treatment and sudden cardiac death has raised concern. A recent epidemiological study found a slight increase in sudden cardiac death with TCA doses greater than 100 mg/day [41]. Therefore caution is recom-mended for older patients, particularly those with cardiovas-cular risk factors [3,27].
Serotonin–noradrenaline reuptake inhibitors Venlafaxine 150–225 mg/day and duloxetine 60–120 mg/day [7,8,42] are significantly effective in PPN (P 0.0001), with a combined Reliability of 128. The Net Gain, however, is comparatively low: 16%. Duloxetine has been shown to improve quality of life and sleep in a large, class-I RCT [43].
In a head-to-head comparison, venlafaxine was as efficacious as the TCA imipramine [44].
Serotonin–noradrenaline reuptake inhibitors (SNRI) are a better option than tricyclics in patients with cardiac disease [7]. The relative risk for withdrawal is not significantly dif-ferent from placebo and there is no need for drug-level 48 Part 2: Neurological symptoms/problems
Chapter 7: Neuropathic pain 49
Table 7.1 Treatments for painful polyneuropathies.
Drugs Sample Benefit with Benefit with Relative Harm with Harm with Relative Reliability
size active control Risk active control Risk and
(trials) (range) (range) (95% CI) (range) (range) (95% CI) Net Gain
TCA 564 56.6% 11.6% 4.9 (3.4–7) 8.9% 2.1% 4.3 (1.7–11) 77 38
(11) (37–89) (0–24) P 0.0001 (0–24) (0–6) P 0.0008
SNRI 1013 51.8% 28.5% 1.8 (1.4–2.1) 11.2% 4.0% 2.8 (1.6–4.9) 128 16
(4) (27–63) (7–35) P 0.0001 (9–20) (4–5.3) P 0.0001
SSRI 162 43.2% 28.4% 1.5 (1–2.3) 5.4% 2.2% 2.5 (0.5–13) 24 –
(3) (20–50) (15–41) ns (0–6) (0–4) ns
PGB/GBP 797 50.3% 20.7% 2.4 (1.9–3) 8.5% 4.4% 1.9 (1.1–3.4) 101 26
(5) (43–61) (14–31) P 0.0001 (6.5–11) (2.9–6.7) P 0.022
NaCB 282 60.1% 20.8% 2.9 (2.1–4.1) 15.3% 4.1% 3.7 (1.5–8.9) 32 22
(3) (48–74) (18–26) P 0.0001 (0–28) (0–8) P 0.019
LTG 59 44.4% 17.9% 2.5 (1–6.1) 6.9% 6.7% 1.0 (0.2–6.9) 10 26
(1) P 0.044 ns
Topiramate 1092 45.7% 23.0% 1.99 (1.3–3) 24.3% 8.3% 2.9 (1.5–5.7) 50 6
(2) P 0.0002 P 0.0005
Valproate 130 56.1% 13.8% 4.1 (2.1–8) 4.6% 1.5% 3.0 (0.3–28) 23 39
(2) (26–83) (10–18) P 0.0001 (3–6) (0–3) ns
Opioids 300 69.4% 27.4% 2.5 (1.8–3.5) 15.2% 4.7% 3.2 (1.4–7.3) 80 32
(3) (41–80) (10–37) P 0.0001 (14–16) (1.5–9) P 0.0033
Mexiletine 158 72.7% 59.6% 1.2 (0.9–1.6) 9.1% 8.5% 1.1 (0.4–3.2) 25 –
(2) (12–87) (33–70) ns (8–13) (3–20) ns
NMDA 106 58% 27.5% 2.1 (1.3–3.5) 1.8% 0% 1 13 29
(3) (47–68) (0–37) P 0.0025 (0–4.3) (0–0) ns
Capsaicin 439 59.5% 45.9% 1.3 (1.1–1.5) 11.9% 2.8% 4.2 (1.6–11) 42 5
(5) (47–89) (18–65) P 0.0045 (7–13) (0–4) P 0.0017
Outcome measure of benefit: number of patients with at least 50% pain relief. Outcome measure of harm: number of drops out due to adverse events. In all instances control is placebo.
Reliability: a metric based on quality of evidence and sample size (see Methods).
Net Gain: a metric based on the relative benefit and harm in a trial where Net Gain (% patients with benefit with active minus % patients with benefit with placebo) minus (% patients with harm with active minus % patients with harm with placebo); it only applies to treatments significantly different from placebo. P-value from Fisher’s exact test.
TCA: tricyclic antidepressants (amitriptyline 75–90 mg, clomipramine 75 mg, desipramine 200 mg, imipramine 100–200 mg, nortriptyline 30 mg, and the tetracyclic maprotiline 75 mg). SNRI: serotonin–noradrenalin reuptake inhibitors (duloxetine 60–120 mg, venlafaxine 150–225 mg). SSRI:
selective serotonin reuptake inhibitors (citalopram 40 mg, fluoxetine 40 mg, paroxetine 40 mg). PGB/GBP: presynaptic calcium-channel modulators (gabapentin (GBP) up to 3600 mg; pregabalin (PGB) 150–600 mg). NaCB: sodium-channel blocking antiepileptic drugs (carbamazepine
(CBZ) 200–600 mg, oxcarbazepine (OXC) 600–1800 mg, phenytoin 300 mg).
LTG: lamotrigine, various-action antiepileptic drug (50–400 mg). Another study in 100 patients with mixed neuropathic pains found no difference between LTG 200 mg and placebo [31].
Topiramate: various-action antiepileptic drug (100–400 mg). Two high-quality, very ample sample size; one, resulting in topiramate placebo, had no calculation of responders [32].
Valproate: various-action antiepileptic drug (1000–1500 mg). Opioids: predominantly acting on mu-opioid receptor (oxycodone 20–80 mg, tramadol 200–400 mg). Mexiletine: antiarrhythmic drug (225–675 mg).
NMDA: N-methyl-D-aspartate antagonists of the NMDA receptor (dextromethorphan 400 mg, memantine 55 mg). In two studies the outcome measure was not 50% pain relief and in one the control group had lorazepam instead of placebo [7,8,33]. Capsaicin, topical: 0.075% cream q.i.d.
monitoring. The most frequently observed adverse events with duloxetine are nausea, somnolence, dry mouth, increased sweating, loss of appetite, and weakness [43]. Although immediate release venlafaxine is associated with adverse CNS and somatic symptoms such as agitation, diarrhoea, increased liver enzymes, hypertension, and hyponatremia [45], the extended release formulation appears to be far more tolerable, the main side effects being gastrointestinal disturbances [44,46].
The optimal dosage of duloxetine is 60 mg/day: 120 mg/day is no better than 60 mg/day and 20 mg/day is ineffective (class I:
32,59). Only high doses of venlafaxine (150–225 mg/day) are effective [7].
Selective serotonin reuptake inhibitors
Paroxetine, fluoxetine, and citalopram have been evaluated in one small-sample class-II RCT each [7,8]. The combined Reliability is low: 24, the efficacy is not significantly different from placebo. It is worth mentioning, however, that paroxe-tine 40 mg/day was significantly better than placebo, with a Net Gain of 35%, in one 20-patient, cross-over RCT [47].
Presynaptic calcium-channel modulators (PGB/GBP) Both pregabalin (PGB) 300–600 mg/day and gabapentin (GBP) 1800–3600 mg/day have good evidence for efficacy in PPN, with several high-quality RCTs [48,49,50,51]. These drugs relieve the pain of diabetic PPN consistently across trials, with a combined Reliability of 101 and Net Gain of 26%. Some of the initial PGB trials were flawed by exclu-sion of GBP non-responders, but two more recent class-I RCTs that did not profit from this kind of enriched enrol-ment still reported a similar efficacy [52,53]. The two drugs have never been compared head-to-head; an indirect comparison between placebo-controlled trials shows similar Net Gains for GBP and PGB. One head-to-head class-II study compared GBP (1800 mg/day) to amitriptyline (75 mg/day):
because of an insufficient sample size, the relative efficacy and tolerability of these drugs could not be definitively assessed [54]. Significant improvement of health-related quality of life and sleep has been documented for GBP in one class-I RCT [48] and for PGB in three class-I RCTs [49,50,52]. The most common side effects of GBP and PGB include dizziness, somnolence, peripheral oedema, and dry mouth, with a similar frequency for both drugs. While GBP is widely accepted as highly tolerable even at high dosages (2400 mg) [20,21], the reports on PGB change remarkably with the daily dose: with 150–300 mg there is almost no dif-ference with placebo [49,53], while the withdrawal rate reaches 20% with 600 mg [52,55].
Sodium-channel blockers
Three small cross-over double-blind trials, published some 30 years ago, reported significant effects of phenytoin and carbamazepine (CBZ) in diabetic PPN, but their methods
and reporting do not live up to current standards [7,8].
Oxcarbazepine (OXC) data were equivocal in PPN, with some unpublished or open-label trial evidence [56]. However, in a recent double-blind parallel-group placebo trial of 16-week duration, OXC (300–1800 mg/day) was moderately effica-cious in diabetic PPN [57]. For the NaCB class, the mean Net Gain is good (22%), but the overall Reliability is very low:
32. One small class-II study reported similar efficacy of CBZ and nortriptyline–fluphenazine, but the small sample size (n 16) might prevent disclosing a difference [58]. In gen-eral, NaCB drugs in PPN do not seem as efficacious as they are in trigeminal neuralgia. CBZ entails frequent adverse events, which include sedation, dizziness, gait abnormalities.
Liver enzymes, blood cells, and platelets must be monitored for at least one year, because of possible toxic effects. Induction of microsomal enzyme systems may influence the metabo-lism of several drugs. In contrast to CBZ, OXC does not entail enzyme induction and there is little risk for crossed cuta-neous allergy. In the first months of treatment, sodium levels must be monitored because OXC induces hyponatraemia, about 6% in the elderly [59]. As regards other side effects, although a better tolerance has been claimed with OXC 50 Part 2: Neurological symptoms/problems
Painful polyneuropathy
0 25 50 75 100
0 25 50 75 100
Reliability
Net Gain
Capsaicin
TCA
SSRI
PGB/GBP
SNRI NaCB
Lamotrigine
Topiramate Valproate
Mexiletine NMDA
Opioids
Figure 7.1 Diagram Reliability/Gain in PPN.
X-axis: Reliability of the evidence, based on quality and sample size of the available trials (see text). Y-axis: Net Gain of active over control both in terms of efficacy and tolerability (see text). Both measures are normalized to maximum and minimum value found in PPN. Drugs in the upper-right quadrant are most reliably efficacious and tolerable, those in the left half are provided with lower-level evidence, those in the lower half are less efficacious or less tolerable. For instance, valproate would be most effective but has poor evidence to support its effectiveness, Serotonin–noradrenaline reuptake inhibitors (SNRI) have top-level evidence but are, comparatively, moderately effective.
compared with CBZ [7,25], this notion lacks consistent evi-dence from class-I trials. In a recent trial in diabetic PPN, 27.5% of the OXC group discontinued treatment due to cen-tral or gastrointestinal side effects versus 8% with the placebo [57]. Both drugs should be initiated with low dosages and slowly increased up to efficacy or intolerable side effects.
Effective dosages range from 200–1200 mg/day for CBZ and 600–1800 mg/day for OXC.
Lamotrigine
Lamotrigine (LTG) up to 400 mg/day, was studied in one high-quality, small sample-size RCT [60], but the difference in pain compared with placebo was only weakly significant (P 0.047). Furthermore, LTG 200 mg/day was found to be equivalent to placebo (Net Gain 0%) in a class-I study in 100 patients with various peripheral neuropathic pains [31]. Side effects of LTG include dizziness, nausea, headache, and fatigue [7,8]. It may induce potentially severe allergic skin reactions.
In a meta-analysis collecting data from 572 patients, 9% of patients were withdrawn because of major adverse events, most commonly rash (class I: 9). To minimize the occurrence of cutaneous rashes, a very slow dose titration is recom-mended: treatment should be initiated with 25 mg daily and increased by 25 mg every other week. The analgesic dosages of LTG range from 200–400 mg/ day.
Valproate
Data about valproate are controversial, because it gave good pain relief results in two class-II studies from the same group [61,62], whereas the drug was no better than placebo in a third, class-I study [63]. Hence its potential in PPN needs further evidence.
Topiramate
Topiramate 100–400 mg/day has been assessed in two class-I RCTs in over 1000 patients with diabetic PPN [32,64]. class-In one it was very weakly efficacious (Net Gain 6%) and in the other it did not prove better than placebo.
Opioids
Only two RCTs assessed a pure opioid (oxycodone) in PPN.
Both were high-quality and demonstrated that controlled release (CR) oxycodone 20–80 mg/day is efficacious and tol-erable [65,66], with a Net Gain of 44%. In these trials, how-ever, patients previously receiving opioids were allowed to participate, which may enhance the proportion of opioid responders and reduce the incidence of side effects. Also tramadol 200–400 mg/day, a drug with both opioid and monoaminergic effects that is usually classified among the minor opioids, was significantly better than placebo in PPN in two class-I RCTs [67,68]. The Net Gain yielded by tramadol Chapter 7: Neuropathic pain 51
Postherpeutic neuralgia
0 25 50 75 100
0 25 50 75 100
Reliability
Net Gain
Capsaicin Lidocaine
TCA
PGB/GBP Valproate
Opioids
NMDA
Figure 7.2 Diagram Reliability/Gain in PHN.
X-axis: Reliability of the evidence, based on quality and sample size of the available trials (see text). Y-axis: Net Gain of active over control both in terms of efficacy and tolerability (see text). Both measures are normalized to maximum and minimum value found in PHN. Drugs in the upper-right quadrant are most reliably efficacious and tolerable, those in the left half are provided with lower-level evidence, those in the lower half are less efficacious or less tolerable.
Central pain
0 25 50 75 100
0 25 50 75 100
Reliability
Net Gain
Cannabis TCA
PGB/GBP
NaCB Lamotrigine Valproate
Figure 7.3 Diagram Reliability/Gain in CP.
X-axis: Reliability of the evidence, based on quality and sample size of the available trials (see text). Y-axis: Net Gain of active over control both in terms of efficacy and tolerability (see text). Both measures are normalized to maximum and minimum value found in CP. Drugs in the upper-right quadrant are most reliably efficacious and tolerable, those in the left half are provided with lower-level evidence, those in the lower half are less efficacious or less tolerable.
(27%), however, is far lower than that of oxycodone. The combined Reliability is 80, the Net Gain 32%. The two largest, high-class, trials that demonstrated efficacy of CR oxycodone and tramadol [65,67] also found these drugs ineffective on quality of life and comorbidities. The most common side effects of opioids are constipation, sedation, and nausea. The risk of cognitive impairment has been reported to be negligi-ble and the side effect profile good, particularly for oxycodone [65,66,69,70,71]. However, less than 20% of patients con-tinue with opioids after 1 year, because of an unfavourable balance between side effects and efficacy [72]. Because of tolerability and tolerance problems in the long term, recent European recommendations indicate that opioids should be considered for chronic non-cancer pain as second line, if other reasonable therapies fail to provide adequate analgesia [7,73]. Tramadol has been reported to induce dizziness, dry mouth, nausea, constipation, and somnolence with signifi-cantly more dropouts compared to placebo [68,70,74].
There is an increased risk of seizures in patients with a his-tory of epilepsy or receiving drugs which may reduce the seizure threshold. Serotonergic syndrome may occur if tramadol is used as an add-on treatment to other serotoner-gic medications (particularly selective serotonin reuptake inhibitors (SSRIs)).
Mexiletine
It is an antiarrhythmic drug, did not yield significant pain relief in four class I–II trials in PPN [7,8].
NMDA-antagonists
Memantine has not shown convincing efficacy in PPN, while pain relief was found for the weak N-methyl-D -aspar-tate (NMDA)-antagonist dextromethorphan in two small trials [8,33]. The combined Net Gain for this drug class is high (29%) but Reliability is low: 13.
Topical capsaicin
Across five class I–II studies [7,8] there is inconsistent evi-dence that capsaicin provides a clinically noticeable pain relief in PPN (the Net Gain is 5% only). Furthermore the intense burning sensation caused by this agent decreases compliance and may cause unblinding.
Combination therapy
The usefulness of combination therapy has been assessed in only two RCTs. The largest one, which also included patients with PHN, was a class-I study demonstrating synergistic effects of GBP–morphine combination, with better analgesia at lower doses of each drug than either as a single agent [75]. The other study, class II, showed the superiority of GBP–venlafaxine combination on pain, mood, and quality of life when compared with GBP plus placebo, but the sam-ple was 11 patients only [51].
Practical recommendations
As summarized in Figure 7.1, three drug classes lie in the upper-right quadrant of higher Reliability of evidence and higher Net Gain over placebo, and should therefore be considered first line in PPN: Opioids, PGB/GBP, and TCA.
The choice among these drugs is subject to several consid-erations that are non-quantitative but must be taken into account in clinical practice. For example, an elderly patient with cardiovascular risks factors should not take TCA. A patient with a severe limitation in quality of life should try first PGB (best evidence for quality of life and comorbidities) rather than opioids (evidence for ineffectiveness on quality of life). A patient with an overt depression will probably receive an additional therapeutic gain with antidepressants.
In a patient with a particularly severe pain that cannot wait for slow titration times it is better to try PGB rather than GBP.
In case of failure, because the mechanisms of action of these three drug classes are completely different, it is reasonable to try – unless contraindicated – all three.
Dosages of opioids should be titrated individually up to efficacy and according to side effects; effective doses for oxycodone range 20–80 mg/day. Tramadol should be initiated at low dosages, particularly in the elderly patient (25 mg once daily) and then titrated as tolerated; the effec-tive dosages range 200–400 mg/day. Effeceffec-tive dosages range 1200–3600 mg/day for GBP and 150–600 mg/day for PGB.
GBP needs slow individual titration with initial dosages of 300 mg/day (or less in elderly patients) while PGB can be titrated more rapidly and has a short onset of action (less than 1 week); whereas GBP should be administered t.i.d., PGB can be administered b.i.d. TCA should be initiated at low dosages (amitriptyline 10–25 mg in a single dose taken at bedtime) and then slowly titrated, as tolerated. Effective dosages are highly variable from one subject to another, the average dosage for amitriptyline being 75 mg/day, that for nortriptyline 30 mg/day. Whether TCA blood concentrations should be measured is still controversial [7,27].