Fig. 14.1
Identification and inclusion of studies
Table 14.1
Characteristics of included studies
Drug class | Trial | Active drug | Daily dose (mg) | N | Age (mean) | Design | Jadad score | Con-cealment | ITT | Treatment period | Follow-up (efficacy of treatment) |
|---|---|---|---|---|---|---|---|---|---|---|---|
Topical treatment | |||||||||||
Capsaicin | Capsaicin study group, [71] | 0.075% capsaicin cream | Apply the cream 3 times a day | 277 | 60 | Parallel | 4 | NM | Yes (for PGE) | 8 weeks | Upon completing treatment |
Isosorbide dinitrate spray | Yuen et al. [68] | Isosorbide dinitrate (ISDN) spray 30 mg | Spray both feet with 30 mg of ISDN before bedtime | 24 | 63.7 | Crossover, 2-week washout | 4 | NM | No | 4 weeks | Upon completing treatment |
Glyceryl trinitrate spray | Agrawal et al. [69] | Glyceryl trinitrate (GTN) spray | Spray both feet once before bedtime | 48 | 58 (group A) 59 (group B) | Crossover, 2-week washout | 4 | NM | No | 4 weeks | Upon completing treatment |
Agrawal et al. [70] | Glyceryl trinitrate (GTN) spray | Spray both feet once bedtime | 40 | Parallel | 4 | NM | No | 4 weeks | Upon completing treatment | ||
Oromucosal spray | Selvarajah et al. [67] | Sativex (tetrahydrocannabinol 27 mg/ml and cannabidiol 25 mg/ml) | Pump-action spray sublingually up to 4 times a day | 30 | 58.2 (Sativex) | Parallel | 4 | NM | Yes | 10 weeks | Upon complete treatment |
54.4 (Placebo) | |||||||||||
Oral treatment | |||||||||||
Anticonvulsant | Rull et al. [44] | Carba-mazepine | 200–600 | 30 | 54.2 | Crossover, no washout | 4 | NM | No | 2 weeks | Upon completing treatment |
Backonja et al. [42] | Gabapentin | 3,600 | 165 | 53 | Parallel | 5 | NM | Yes | 8 weeks | Upon completing treatment | |
Rauck et al. [50] | Lacosamide | 100–400 | 119 | 55 | Parallel (phase 2 study) | 5 | Yes | Yes | 8 weeks | Upon complete treatment | |
Shaibani et al. [51] | Lascosamide | 200/400 | 331 | 59.8 | Parallel (phase 3 study) | 5 | Yes | Yes | 18 weeks | Upon complete treatment | |
Wymer et al. [52] | Lascosamide | 200/400 | 277 | 58.2 | Parallel | 5 | Yes | Yes | 18 weeks | Upon complete treatment | |
Ziegler et al. [53] | Lascosamide | 400/600 | 357 | 57.9 | Parallel | 4 | NM | Yes | 18 weeks | Upon complete treatment | |
Eisenberg et al. [43] | Lamotrigine | 25–400 | 59 | 55 | Parallel | 3 | NM | No | 10 weeks | Upon completing treatment | |
Dogra et al. [54] | Oxcarbazepine | 1,445 (mean) | 146 | 60 | Parallel | 5 | Yes | Yes | 16 weeks | Upon completing treatment | |
Beydoun et al. [55] | Oxcarbazepine | 600/1,200/1,800 | 347 | 60 | Parallel | 5 | Yes | Yes | 16 weeks | Upon completing treatment | |
Rosenstock et al. [46] | Pregabalin | 300 | 146 | 59.7 | Parallel | 5 | Yes | No | 8 weeks | Upon completing treatment | |
Richter et al. [47] | Pregabalin | 150/600 | 246 | 57 | Parallel | 5 | NM | Yes | 6 weeks | Upon completing treatment | |
Lesser et al. [45] | Pregabalin | 75/300/600 | 337 | 59.9 | Parallel | 5 | Yes | Yes | 5 weeks | 5 weeks for double blind period | |
Arezzo et al. [48] | Pregabalin | 600 | 167 | 58 | Parallel | 5 | Yes | Yes | 12 weeks | Upon complete treatment | |
Satoh et al. [49] | Pregabalin | 300/600 | 314 | 61.3/62.2 | Parallel | 4 | Yes | Yes | 12 weeks | Upon complete treatment | |
Kochar et al. [40] | Sodium valproate | 1,200 | 57 | 56 | Parallel | 3 | Yes | Yes | 4 weeks | Upon completing treatment | |
Kochar et al. [41] | Sodium valproate | 1,000 | 43 | 55 | Parallel | 5 | NM | No | 3 months | Upon completing treatment | |
Antidepressant | |||||||||||
TCA | Max et al. [26] | Amitriptyline | 25–100 | 37 | 57 (median) | Crossover, no washout | 4 | NM | No | 6 weeks | Upon completing treatment |
Max et al. [23] | Desipramine | Mean 201 | 24 | 62 (median) | Crossover, no washout | 4 | NM | No | 6 weeks | Upon completing treatment | |
Kvinesdal et al. [25] | Imipramine | 100 | 15 | 54 | Crossover, no washout | 4 | NM | No | 5 weeks | Upon completing treatment | |
SSRI | Sindrup et al. [24] | Citalopram | 40 | 18 | 56 (median) | Crossover, 1-week washout | 4 | NM | No | 3 weeks | Upon completing treatment |
Dual reuptake inhibitor of 5-HT and NE | Rowbotham et al. [29] | Venlafaxine | 75/150–225 | 164 | 59/58 | Parallel | 4 | NM | Yes | 6 weeks | Upon complete treatment |
Goldstein et al. [27] | Duloxetine | 20/60/120 | 457 | 60 | Parallel | 4 | Yes | Yes | 12 weeks | Upon completing treatment | |
Raskin et al. [28] | Duloxetine | 60/120 | 348 | 58.8 | Parallel | 5 | Yes | Yes | 12 weeks | Upon completing treatment | |
Ion channel blocker | Dejgard et al. (1998) | Mexiletine | 10 mg/kg | 16 | 50 (median) | Crossover, 4-week washout | 3 | NM | No | 10 weeks | Upon completing treatment |
Oskarsson et al. [64] | Mexiletine | 225/450/675 | 126 | 53.5 | Parallel | 3 | NM | No | 3 weeks | Upon completing treatment | |
Wright et al. [65] | Mexiletine | 600 | 31 | 50 | Parallel | 3 | NM | Yes | 3 weeks | Upon completing treatment | |
NMDA antagonist | Nelson et al. [66] | Dextro-methorphan | Mean 381 | 14 | 54 (median) | Crossover, 1-week washout | 5 | NM | No | 6 weeks | Upon completing treatment |
Opioid | Gimbel et al. [56] | Controlled-release oxycodone | 10–120 | 159 | 59 | Parallel | 5 | Yes | Yes | 42 days | Upon completing treatment |
Watson et al. [57] | Controlled-release oxycodone | 10–80 | 45 | 63 | Crossover, no washout | 5 | Yes | Yes | 4 weeks | Upon completing treatment | |
Tramadol | Harati et al. (1999) | Tramadol | 200–400 | 125 | 59 | Parallel | 5 | Yes | Yes | 42 days | Upon completing treatment |
Duration of Treatment in the Studies
As the longest treatment period in the present review was 18 weeks, the studies may not reflect the drugs’ efficacy and tolerability in real life, especially in patients with chronic pain. Although we acknowledge that it is difficult to conduct long-term (>6 months), double-blind clinical trials, such information can be obtained through long-term, open-label studies and clinical observation. Several long-term, open-label studies have investigated oxcarbazepine [17], duloxetine [18] and tramadol [19] for 6–12 months. Although approximately 20%, 20–27% and 11% of patients using oxcarbazepine, duloxetine and tramadol respectively withdrew from the long-term studies, their results showed good pain-relieving effects. As all drugs have side effects, strategies to minimise them and optimise treatment effects should be explored and employed.
Impact on Quality of Life and Physical Functioning
Quality of life is multidimensional which covers five dimensions including physical well-being, material well-being, social well-being, emotional well-being, and development and activity [20]. PDN has a significant impact on patient’s quality of life. Galer and colleagues (2000) reported that more than 50% of 104 patients with painful DPN had impaired physical mobility, working ability, sleep quality and psychosocial well-being [21]. Another study found that patients with painful DPN had poor sleep quality, perceived decreased physical mobility, were less energetic and had more emotional problems compared with those with asymptomatic DN [22]. Davies and colleagues (2006) used a neuropathy and foot ulcer-specific quality of life instrument and found that patients with painful DSPN had significantly poorer quality of life compared to those without pain [3].
Treatment Efficacy in Quality of Life and Physical Functioning
The effect of pharmacological management on quality of life and physical functioning was explored with data available in the retrieved reports. Various scales were adopted to measure quality of life and physical functioning in the retrieved reported such as SF-36, Brief Pain Inventory and Pain and Disability Indicator. Significant improvement in quality of life and physical functioning in antidepressants, anticonvulsants and opioids groups were reported, which indicated that these medicines yield improvement of quality of life and physical functioning besides pain reduction. The effect of different classes of medicines on quality of life will be further discussed in this chapter.
Impact of Different Classes of Drugs
Antidepressants
Although the primary role of antidepressants is to treat depression, they are also commonly used in pain management, where their effect is thought to be related to a reduction in the depression-related pain component. Antidepressants can be divided into two groups: typical and atypical antidepressants. Typical antidepressants include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs). Atypical antidepressants include norepinephrine and dopamine reuptake inhibitors (NDRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and serotonin-2 antagonist/reuptake inhibitors (SARIs).
Our review of the literature identified seven trials with a total of 1,063 patients that investigated desipramine [23], citalopram [24], impramine [25], amitriptyline [26], duloxetine [27, 28] and venlafaxine [29]. Three of the studies investigated tricyclic antidepressants (TCAs), three investigated serotonin noradrenaline reuptake inhibitors (SNRIs) and one investigated serotonin reuptake inhibitors (SSRIs). Four were crossover studies with 3- to 6-week treatment periods [23–26] and three used a parallel-group design with 6- to 12-week treatment periods [27–29]. Amongst the four crossover studies, only one included a 1-week washout period; the data from the first treatment period of this study were extracted and analysed [24]. Venlafaxine 75 mg and Duloxetine 20 mg and 120 mg were excluded from the pooled analysis.
TCAs have a moderate impact on improving pain but do carry a risk of adverse event making them difficult for some patients to tolerate. TCAs also have little evidence-based support of positive impact on quality of life for patients with PDN. For TCAs, the pooled NNT for a notable improvement in the global assessment and moderate pain relief was 1.56 (95% Confidence Interval (CI) 1.31–1.95); there was a slight variation between studies and no significant heterogeneity (I 2 = 1.5%, p = 0.36). For SNRIs, the pooled Number Needed to Treat (NNT) for a 50% pain reduction was 4.51 (3.36–6.86); there was no variation between studies and no significant heterogeneity (I 2 = 0%, p = 0.93). For antidepressants, the pooled NNT for a 50% pain reduction was 3.5 (95% CI 2.84–4.54); there was moderate variation between studies and no significant heterogeneity (I 2 = 51%, p = 0.06). Table 14.2 shows the NNT for individual antidepressants.
Table 14.2
Efficacy of individual antidepressants
Treatment | Route | Number of studies | Treatment (n/N) | Placebo (n/N) | NNT (95% CI) |
|---|---|---|---|---|---|
Amitriptyline 25–150 mg (TCA)a | Oral | 1 | 23/29 | 0/29 | 1.26 (1.06–1.55) |
Imipramine 100 mg (TCA)b | Oral | 1 | 7/12 | 0/12 | 1.71 (1.16–3.29) |
Desipramine 12.5–250 mg (TCA)a | Oral | 1 | 11/20 | 2/20 | 2.22 (1.42–5.12) |
Venlafaxine ER 150–225 mgc | Oral | 1 | 46/82 | 23/69 | 4.39 (2.62–13.7) |
Duloxetine 60 mgc | Oral | 2 | 112/227 | 63/228 | 4.61 (3.29–7.7) |
Duloxetine 120 mgc,d | Oral | 2 | 101/227 | 63/228 | 5.93 (3.91–12.23) |
Duloxetine 20 mgc,d | Oral | 1 | 46/115 | 29/115 | 6.76 (3.74–35.5) |
Citalopram 40 mg (SSRI)c | Oral | 1 | 3/15 | 1/15 | 7.5 (NNTH 9.5–¥ to NNTB 2.69) |
Venlafaxine ER 75 mgc,d | Oral | 1 | 32/80 | 23/69 | 15 (NNTH 11.37–¥ to NNTB 4.52) |
Compared with TCAs, Duloxetine does have evidence-based support of positive impact on quality of life for patients with PDN. Duloxetine 120 mg/day compared to those treated with placebo had significant improvement in all domains of except physical domain, while using duloxetine 60 mg/day improved mental health domain only [27]. Raskin and colleagues (2005) reported significant improvement in general activity, mood, walking ability, normal work, relationships, sleep and enjoyment of life when compared between duloxetine 120 mg/day and placebo group with Brief Pain Inventory (BPI) [28]. There was significant improvement in general activity, walking ability, normal work, sleep and enjoyment of life in duloxetine 60 mg/day group when compared to placebo group [28].
For TCAs, the pooled NNT for adverse event related withdrawal was 19 (95% CI NNTH 55.95–∞ to NNTB 8.12); there was no variation between studies and no significant heterogeneity (I 2 = 0%, p = 0.77). For SNRIs, the pooled NNT for adverse event related withdrawal was 22.29 (12.16–133.16); there was no variation between studies and no significant heterogeneity (I 2 = 0%, p = 0.84). For antidepressants, the pooled NNT for adverse event related withdrawal was 20.13 (95% CI 12.19–57.79); no heterogeneity was detected (I 2 = 0%, p = 0.98). Three patients in the Venlafaxine ER 75 and 150/225 groups withdrew from the study due to treatment-related atrial fibrillation, ventricular extrasystoles and 1° AV block [29]. For TCAs, the most common adverse events leading to withdrawal were dry mouth and sedation. Table 14.3 shows the NNT for adverse event related withdrawal of individual antidepressants.
Table 14.3
NNT for adverse event related withdrawal of individual antidepressants
Treatment | Route | Number of studies | Treatment (n/N) | Placebo (n/N) | NNT (95% CI) |
|---|---|---|---|---|---|
Duloxetine 20 mga | Oral | 1 | 5/115 | 6/115 | 115 (NNTH 15.66–¥ to NNTB 21.53) |
Amitriptyline 25–150 mg | Oral | 1 | 3/37 | 2/37 | 37 (NNTH 11.47–¥ to NNTB 7.08) |
Venlafaxine ER 150–225 mg | Oral | 1 | 6/82 | 3/81 | 27 (NNTH 29.72–¥ to NNTB 9.44) |
Duloxetine 60 mg | Oral | 2 | 20/230 | 9/231 | 20.8 (10.85–259.72) |
Venlafaxine ER 75 mga | Oral | 1 | 8/82 | 3/81 | 16.5 (NNTH 63.53–¥ to NNTB 7.31) |
Imipramine 100 mg | Oral | 1 | 1/15 | 0/15 | 15 (NNTH 16.79–¥ to NNTB 5.18) |
Desipramine 12.5–250 mg | Oral | 1 | 2/24 | 0/24 | 12 (NNTH 36.71–¥ to NNTB 5.16) |
Duloxetine 120 mga | Oral | 2 | 36/229 | 9/231 | 8.51 (5.86 –15.53) |
Citalopram | Oral | 1 | 2/16 | 0/18 | 8 (NNTH 27–¥ to NNTB 3.48) |
Summary of Impact of Antidepressant on Patients
Our review of the current data shows that antidepressants have a positive impact on patients’ diabetic neuropathic pain levels with a relatively low NNT. When considering both typical and atypical antidepressants, only 3.5 patients needed to be treated with antidepressants for one to have a moderate (50%) pain reduction, this number decreases to only 1.56 patients needing to undergo treatment with TCAs for one to have a moderate decrease in pain. Conversely, the NNT to reach adverse event related withdrawal from treatment is much higher at 20.13. TCAs are shown to be more tolerable than atypical antidepressants as there was no significant difference between TCAs and placebo in adverse events while the NNT for adverse events was 22.29 for SNRIs. Therefore, the evidence shows that with widespread use of antidepressants for treatment of PDN, more patients will experience pain reduction than intolerable side effects. Although evidence supporting the impact of TCAs on patient quality of life is limited, Duloxetine does positively impact patient quality of life. In addition to pain reduction, Duloxetine treatment exhibited significant improvement in general activity, mood, walking ability, normal work, relationships, sleep and enjoyment of life [28].
Anticonvulsants
Epilepsy is the primary therapeutic indicator for anticonvulsant drugs. However, many anticonvulsant drugs, including gabapentin, carbamazepine, valproic acid, clonazepam, phenytoin, lamotrigine and pregabalin have demonstrated positive effects on neuropathic pain reduction. Although the mechanism of action of these anticonvulsants for pain relief has not been fully elucidated, it is proposed to be related to the inhibition of sodium channel activity [30–32], ectopic discharge [33, 34], calcium channel blockade [35–37], increased GABA concentration [38, 39] and inhibition of NMDA receptor activity [39].
Our literature review identified 16 trials with a total of 3,141 patients that investigated anticonvulsants, including sodium valproate [40, 41], gabapentin [42], lamotrigine [43], carbamazepine [44], pregabalin [45–49], lacosamide [50–53] and oxcarbazepine [54, 55]. A crossover design was used in the carbamazepine trial. The treatment periods ranged from 2 weeks to 18 months. No efficacy data were extracted form the study of sodium valproate [41]. Data on 300 mg pregabalin [45, 46], 1,200 mg oxcarbazepine [55] and the first treatment period for the carbamazepine trial [44] were extracted for meta-analysis. Data on pregabalin 600 mg, lacosamide 200 and 600 mg were analysed separately.
Anticonvulsants do have the potential to positively impact pain reduction and appear to also improve quality of life for patients with PDN. However, there does exist the risk of adverse events that may make anticonvulsants a difficult option for patients with PDN. For anticonvulsants, the pooled NNT for a 50% reduction in pain was 5.58 (95% CI 4.44–7.49). There was mild variation between studies and no significant heterogeneity (I 2 = 30%, p = 0.16). The incidence of adverse events was similar for slow and standard titration in 6-week titration of lascosamide 400 mg/day [53]. Table 14.4 shows the efficacy results of individual anticonvulsants. Lacosamide 200 and 600 mg did not produce significant pain reduction compared to placebo.
Table 14.4
Efficacy of individual anticonvulsants
Treatment | Route | Number of studies | Treatment (n/N) | Placebo (n/N) | NNT (95% CI) |
|---|---|---|---|---|---|
Carbamazepine 600 mga | Oral | 1 | 7/14 | 0/16 | 2 (1.3–4.2) |
Sodium valproate 1,200 mga | Oral | 1 | 7/14 | 2/16 | 2.67 (1.46–14.92) |
Gabapentin 900–3,600 mgb | Oral | 1 | 47/79 | 25/76 | 3.76 (2.4–8.72) |
Pregabalin 600 mgc,d | Oral | 4 | 127/290 | 76/389
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