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Br J Clin Pharmacol. Jun 2000; 49(6): 574–579.
PMCID: PMC2015036

Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study

Abstract

Aims

To assess the analgesic efficacy of topical administration of 3.3% doxepin hydrochloride, 0.025% capsaicin and a combination of 3.3% doxepin and 0.025% capsaicin in human chronic neuropathic pain.

Methods

A randomized, double-blind, placebo-controlled study of 200 consenting adult patients. Patients applied placebo, doxepin, capsaicin or doxepin/capsaicin cream daily for 4 weeks. Patients recorded on a daily basis overall pain, shooting, burning, paraesthesia and numbness using a 0–10 visual analogue scale during the week prior to cream application (baseline levels) and for the 4 week study period. Side-effects and desire to continue treatment were also recorded.

Results

Overall pain was significantly reduced by doxepin, capsaicin and doxepin/capsaicin to a similar extent. The analgesia with doxepin/capsaicin was of more rapid onset. Capsaicin significantly reduced sensitivity and shooting pain. Burning pain was increased by doxepin and by capsaicin and to a lesser extent by doxepin/capsaicin. Side-effects were minor. One patient requested to continue placebo cream, 17 doxepin cream, 13 capsaicin and 9 the combination of doxepin and capsaicin.

Conclusions

Topical application of 3.3% doxepin, 0.025% capsaicin and 3.3% doxepin/0.025% capsaicin produces analgesia of similar magnitude. The combination produces more rapid analgesia.

Keywords: capsaicin, doxepin, neuropathic pain, tricyclic antidepressants

Introduction

Tricyclic antidepressants (TCAs) have an analgesic effect in neuropathic pain [1] and this effect is independent of their antidepressant action [2]. Such an analgesic effect has been demonstrated when amitriptyline [35], desimipramine [68], clomipramine [9, 10] and imipramine [11] are taken orally. TCAs have a variety of effects and these include peripheral as well as the more well known central modes of action; both amitriptyline and desimipramine produce analgesia in the animal formalin test [12, 13] while clomipramine and imipramine reduce response to carrageenin inflammation [14, 15]. It seems that some of the anti-nociceptive effect of amitriptyline is mediated via peripheral adenosine receptors [16].

Capsaicin, whose use as an analgesic was described as long ago as 1850 [17], has a verified analgesic effect in the pain of post herpetic neuralgia [1820], diabetic neuropathy [21, 22] and surgical neuropathic pain [23]. Capsaicin causes release of substance P from C fibre afferent neurones, and repeated application reversibly depletes stores of substance P and therefore reduces pain transmission from peripheral nerve fibres to higher centres [24].

An analgesic effect of the topically applied TCA doxepin in chronic human neuropathic pain has recently been described [25]. With a clinical impression of a synergistic effect when agents from different classes of drugs are coadministered, it was decided to examine the effect of topical administration of capsaicin, doxepin and a mixture of both on chronic human neuropathic pain.

Methods

This was a randomized, double-blind, placebo-controlled study of 200 adult patients with chronic neuropathic pain. Ethics Committee approval was granted and written informed consent obtained from the study patients. For the purposes of this study, neuropathic pain was diagnosed when patients presented with pain which included at least three of the constituent symptoms of neuropathic pain, namely shooting pain, burning, numbness, parasthesiae and sensitivity (allodynia). All patients had pain that was unresponsive to simple or compound codeine containing analgesics or nonsteroidal anti-inflammatory drugs. All patients had tried oral TCAs for their pain and had either been unresponsive or intolerant. Patients were excluded if they had a known sensitivity to doxepin or capsaicin or if they had broken skin over the area where they felt their pain. Patients were asked to record all study measurements for 1 week prior to randomization to provide baseline scores for these parameters. After baseline measurement, patients were randomly allocated, using a computer generated random number list, in equal numbers, to the four study groups (A, B, C, D). Patients in group A received placebo (aqueous cream), group B 3.3% doxepin hydrochloride (2 parts 5% doxepin hydrochloride (Xepin, Bioglan Laboratories Ltd) with 1 part aqueous cream), group C 0.025% capsaicin (Zacin, Elan Pharma) and group D 3.3% doxepin/0.025% capsaicin (1 part 0.075% capsaicin (Axsain, Elan Pharma) to 2 parts 5% doxepin (Xepin, Bioglan Laboratories Ltd). All study creams were white, odourless, had a similar nongreasy texture and they were contained in identical screw top containers marked with the appropriate randomization letter. All cream combinations appeared to mix readily; further investigation is required to assess the stability of the mixtures in terms of physical and chemical compatibility. Patients were instructed to apply a volume of cream approximately equal in size to a grain of rice three times daily to the painful area and to record all study measurements daily for the 4 week study period. A visual representation of the amount of cream to be applied was used to assist concordance. Patients were asked not to wash the application area for 1 h after application, and to ensure that they did wash the application finger to avoid accidental application of study cream elsewhere. At the end of the study period patients were asked to return their study cream container as a check on compliance. If an insufficient volume of cream had been used (arbitrarily set at 50% of contents of container) then these patients were excluded from the study.

Patients were asked to record the average level over the previous 24 h of the following variables using a continuous 0–10 visual analogue score (VAS) which was measured to the nearest 0.1 cm: overall pain, shooting pain, burning pain, numbness, pareasthesia and sensitivity. In addition, they were asked to record side-effects and their desire to stay on the study medication.

Average change in scores with standard deviation and 95% confidence limits (95% CL) were calculated for the prestudy week and each of the 4 study weeks. The significance of changes from baseline levels were assessed using Student's t-test with P < 0.05 being considered significant. Pre-study calculations suggested that 60 patients per group were required to show a 1 point fall (90% power, and 17 to demonstrate a 2 point fall (90% power).

Results

No study subjects were excluded due to known sensitivity to doxepin or capsaicin. One hundred and fifty-one patients (75.5%) provided results (41 placebo, 41 doxepin, 33 capsaicin, 36 doxepin/capsaicin). Non compliance (less than 50% of cream used) was suspected in 18 patients (three placebo, two doxepin, eight capsaicin, five doxepin/capsaicin). Demographic details are shown in Table 1. The duration of pain in the doxepin/capsaicin group was greater than the other groups (P = 0.05).

Table 1
Demographic details (mean (s.d.))

The data for all pain scores were normally distributed and hence parametric tests were used. There were no statistically significant differences in baseline scores for the paramaters measured between the treatment groups: pretreatment overall pain scores were 7.13 in the placebo group, 7.29 in the doxepin group, 7.11 in the capsaicin group and 7.47 in the doxepin/capsaicin group.

Overall pain was unchanged in the placebo group, but fell by 0.9 (95% CL 0.34–1.46) in the doxepin group (P < 0.001), 1.12 (95% CL 0.44–1.8) in the capsaicin group (P < 0.001) and 1.07 (95% CL 0.39–1.75) in the doxepin/capsaicin group (P < 0.001). Statistically significant falls in pain scores were apparent in all three active treatment groups from week 2 of treatment (Figure 1).

Figure 1
Overall pain as measured by a 0 – 10 cm visual analogue scale, 0 = no pain. [filled square] placebo, ♦ doxepin,[filled triangle] capsaicin, • doxepin/capsaicin.

Numbness and pins and needles did not change from baseline measurements in any of the four groups (Figures 2 and and33).

Figure 2
Numbness as measured by a 0 – 10 cm visual analogue scale, 0 = no numbness. [filled square] placebo, ♦ doxepin, [filled triangle] capsaicin, • doxepin/capsaicin.
Figure 3
Parasthesiae as measured by a 0 – 10 cm visual analogue scale, 0 = no pain. [filled square] placebo, ♦ doxepin, [filled triangle] capsaicin, • doxepin/capsaicin.

Scores for burning pain remained at baseline levels of 2.34 in the placebo group but increased in the doxepin group by 2.1 (95% CL 1.62–2.58) after 1 week (P < 0.001) with a decrease from this elevated level by 0.68 (95% CL 0.32–1.04) by week 4 (P < 0.01). There was a similar elevation from baseline in the capsaicin group by 1.6 (95% CL 0.86–2.34) after the first week of treatment (P < 0.01), with a gradual decrease by 0.52 (95% CL −0.42–1.46) after the 4th treatment week. In the doxepin/capsaicin group the elevation from baseline was less substantial, rising by 0.32 after 1 week (95% CL 0.11–0.53) (P < 0.01). There was no decrease in this level as treatment time increased Figure 4.

Figure 4
Burning pain as measured by a 0 – 10 cm visual analogue scale, 0 = no pain.[filled square] placebo, ♦ doxepin, [filled triangle] capsaicin, • doxepin/capsaicin.

Sensitivity was unchanged by placebo or doxepin. Scores for sensitivity fell from the baseline immediately after commencement of capsaicin treatment, with an initial fall of 1.2 (95% CL 0.1–2.3) after the first study week (P < 0.001), with a further gradual further fall by 0.19 (95% CL −0.49–0.87) by week 4 (P < 0.05). In the doxepin/capsaicin group there was an immediate fall from baseline level by 0.95 (95% CL 0.7–1.2) after the first study week (P < 0.01) with no further falls with continued treatment (Figure 5).

Figure 5
Sensitivity as measured by a 0 – 10 cm visual analogue scale, 0 = no pain.[filled square] placebo, ♦ doxepin, [filled triangle] capsaicin, • doxepin/capsaicin.

Shooting pain was unaltered by placebo or doxepin. Application of capsaicin reduced shooting pain from baseline level by 0.75 (95% CL 0–1.5) after 4 weeks (P < 0.001). Shooting pain was reduced by 0.73 (95% C.L. 0.28–1.18) with the doxepin/capsaicin combination (P < 0.001) (Figure 6).

Figure 6
Shooting pain as measured by a 0 – 10 cm visual analogue scale, 0 = no pain.[filled square] placebo, ♦ doxepin, [filled triangle] capsaicin, • doxepin/capsaicin.

In terms of cream preference, it emerged when blinding codes were broken that 1 patient (2.4%) wished to continue with placebo, 17 (41%) with doxepin, 13 (39%) with capsaicin and 9 (25%) with doxepin/capsaicin.

Side-effects were minor. Four patients (9.7%) in the doxepin and 2 (5.5%) in the doxepin/capsaicin group complained of drowsiness, 1 (2.4%) had a skin rash with doxepin, 1 (2.8%) a headache with doxepin/capsaicin and 2 (4.9%) had itch with doxepin. Burning discomfort after cream application was noted by 27 (81%) in the capsaicin group, 22 (61%) in the doxepin/capsaicin group and 4 (17%) in the doxepin group.

Discussion

With any drug treatment there is a compromise between effect and side-effect. Despite the proven efficacy of oral TCAs in neuropathic pain, side-effects are experienced by almost one in three patients [1]. This study demonstrates that topical application of doxepin has an analgesic effect in neuropathic pain and that compared with oral administration, side-effects are less common. The most popular study cream was doxepin despite the fact that that it had less effect on some of the component symptoms of neuropathic pain. It is possible that this patient preference was based on it having the lowest side-effect profile of the active treatment creams.

It is commonly accepted that TCAs have a central mode of action in neuropathic pain, and yet this study and our previous study using topical application [25] both demonstrate an analgesic effect. This analgesia may be due to systemic absorption of the doxepin, a local peripheral effect or a combination of both. A small number of patients complained of drowsiness after use of topical doxepin and similar side-effects have been seen when topical doxepin is used in the treatment of itch associated with ezcema [26, 27]. This consistent reporting of increased incidence of drowsiness with topical application of doxepin when compared with placebo suggests systemic absorption. Further work is needed to measure serum levels of doxepin after topical application and assess correlation to amount applied, area and site of application, concomitent drug administration, and so on.

The analgesia produced takes around 2 weeks to become apparent and this is similar to the time to steady-state concentration after oral dosing [28]. Since these agents have multiple effects these results give no indication of the receptors or level at which doxepin acts.

In contrast to capsaicin, it seemed that doxepin reduced patients’ pain without having a significant effect on the component symptoms of neuropathic pain. Capsaicin, which appeared to be equally analgesic to doxepin also reduced shooting pain and had a profound effect on the patients perception of sensitivity, with a reduction in sensitivity becoming apparent immediately after initial application of the capsaicin. This study used the patients’ impression of sensitivity, or allodynia (pain created by a normally nonpainful stimulus): further work is needed to define whether this effect was on dynamic or static allodynia and this may give a clearer guide as to the specific neural effect of the capsaicin. From a clinical perspective, it is important to define the effect of therapeutic agents not only on overall pain, but also on the component symptoms: which drug, for example, is most effective for shooting pain or pins and needles? In addition, there is a need to define the optimal concentration of doxepin, capsaicin and the combination of both to achieve maximum analgesia and the minimum level of side-effects.

When doxepin is combined with capsaicin there is no augmentation of effect. However, with overall pain, the analgesia seen with capsaicin, doxepin and doxepin/capsaicin is similar after 4 weeks, but the combination had a quicker onset with reduction in pain scores during the first week of application as opposed to the others where analgesia took 2 weeks to achieve. Similarly, capsaicin reduced shooting pain, but this relief was more rapid when doxepin/capsaicin was used.

All the active treatments were associated with an increase in burning pain and this was most marked in the capsaicin group. Patients may have had difficulty differentiating between their underlying burning pain and the burning associated with application of capsaicin. Doxepin also increased burning pain, and while application associated burning discomfort is recognized, clinically it is not common [26, 27]. The doxepin may therefore have exaggerated the underlying burning pain. The combination of doxepin and capsaicin seemed to attenuate the burning associated with application of capsaicin alone.

In conclusion, the topical application of 3.3% doxepin hydrochloride, 0.025% capsaicin and 3.3% doxepin/0.025% capsaicin is associated with analgesia in chronic human neuropathic pain. The extent of analgesia is similar in each group, but is more rapidly achieved with the doxepin/capsaicin combination. 0.025% capsaicin had a marked effect on sensitivity and a lesser effect on shooting pain. Burning pain is increased by doxepin, capsaicin and doxepin/capsaicin, although in the latter group the rise in burning pain is less substantial.

Acknowledgments

5% doxepin cream, 0.025% and 0.075% capsaicin cream were supplied by Bioglan Laboratories Ltd, Hitchen, Hertfordshire.

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