Post-herpetic neuralgia and topical capsaicin

333

Pain, 33 (1988) 333-340 Elsevier PA1 01231

Post-herpetic neuralgia and topical capsaicin C. Peter N. Watson, Ramon J. Evans and Vema R. Watt Smytlre Pain Clinic,

T5runfo

General Hospital,

Un~~e;sity of

Toronto,

Toronto, Ont. M5G X4

(Cunaab]

(Received 17 November 1987, revision received 13 January 1988, accepted 24 January 1988)

s-

Topical 0.025% capsaicin was used to treat 33 patients with post-herpetic neuralgia (PHN). Thirty-nine percent of those entering the trial achieved at least a good result and 55% were improved or better. Fifty-six percent of the 23 patients completing the study had good or excellent pain relief after 4 weeks. Seventy-eight percent of the 23 noted at least some ~provement in pain. Post-caps&in burning was a common, untoward effect in most patients and in about one-third was so unbearable that the trial was terminated prematurely. This treatment appears to be a useful modality in PHN, particularly in the elderly in whom oral medications are often poorly tolerated; however, it does require supervision. A double-blind, controlled trial is now necessary.

Key words: Capsaicin; Post-hetpetic neuralgia

Introduction Post-herpetic neuralgia (PHN) occurs in about 10% of all patients 1 month following herpes zoster (HZ) (21. This incidence is directly related to age, so that over age 60, 50% of cases of HZ may develop this severe pain [3]. A variety of treatment approaches have been suggested but most of these are of limited use and scientifically unproven [lo]. Sixty to 70% will benefit from tricyclic antidepress~ts such as ~t~pty~e [ll], however, these agents have troublesome anticholinergic side effects which limit their usage. A large number of patients are left with continuing, intractably severe pain and newer remedies need to be explored. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the active principle in hot peppers and

Correspondence to: C. Peter N. Watson, Smythe Pain Clinic, Toronto General Hospital, Toronto, Gnt. M5G 2C4, Canada.

0304-3959/88/$03.50

other similar plants of the nightshade family. It was recommended as long ago as 1850 as a treatment for toothache f9f and is chemically similar to eugenol, the active principle of oil of cloves, another old toothache remedy, which is known to produce a long-lasting trigeminal anaesthesia 141. The mechanism of this paradoxical effect of an acrid substance has only lately come to be understood. Capsaicin selectively stimulates and then blocks small diameter, nociceptive sensory afferents from the skin and mucous membranes, many of which utilize substance P, but also somatostatin and possible other neuropeptides, and it is thought that this is the basis of its action [5-8,121. Recently the topical application of capsaicin has been reported to be effective in relieving the pain of PHN in a small, open-label study by Bernstein [l]. We report here a larger study of 33 patients with established PHN performed in order to see if a double-blind, placebo-controlled trial is justified.

0 1988 Elsevier Science Publishers B.V. (Biomedical Division)

I

OF VERBAL

INTENSITY

M

M

F

M

M

F

F

71

85

57

71

65

61

80

4. JW

5. BC

6. BS

I. JL

8. DR

9. AB

10. AC

L TIZ, Ll

RTlO, 11

LTS

L Cs, 6, 7

none

3

amitriptyline 75 mg q.h.s. Percocet 1 daily none

none

3

24

t.i.d.

one Tylenol b.i.d.

Percocet

none

none

one Percocet t.i.d.

ConcQmitant analgesics

none

60

ANALOGUE rating;

SCALES S = severe;

(VAS) AND

VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT

VIS

Baseiine S S U MO S U S S U S S U MO S U MO/S S U MO/S MO U S S U MO/S S U MO/S s U MI MI SA

MI MI SA S S U

MO MO U

MO S U MO MO U

1

Treatment period (weeks)

SAT = satisfaction

24

18

LT3

LVl

12

R V12

105

F

66

3. MG

L T5

F

80

2. WB

48

144

LT5,6

M

59

1. LJ

Duration PI-IN (months)

LT6.7

Dermatome

Sex

Age

Patient

scale;

(VIS), VISUAL

analogue

SCALES

VIS = verbal intensity scale; VAS = visual NR = no response; IC = incomplete.

RESULTS

TABLE SATISFACTION

MI Ml SA

MO S U MO MO U

U S MO U

S S

2

MI Mt SA

NIL NIL SA MI MX SA

3

MO = moderate;

.,

MI MI SA

MI MI SA NIL NIL SA MI MI SA

4

RELIEF

severe burning

IC

*I

,xcasjon3i burning

mritl

severe burning

IC

goitJ

severe burning and skin breakdown

mild burning

mild bunring

IC

excelfent

severe burning

IC

mild burning

none

none

Side effects

SA = satisfied;

NR

NR

Response rating

U = unsatisfied;

PAIN

(SAT) FOR

RATINGS MI = mild;

76

82

80

81

80

61

88

68

73

80

56

69

69

11. CB

12. MH

13. W

14. AR

15. SK

16. PS

17. SF

18. MM

19. PS

20. TO

21.WW

22. EM

23. DD

F

F

F

F

F

F

M

M

F

M

F

F

F

-

..”

154

36

LT4

LVl Tylenol t.i.d.

amitriptyline 125 mg q.h.s.

none

21

LT5,6

LTl,2

4 Tylenol no. 3 daily

7 Tylenol no. 3 daily

24

3

6 Percocet daily

24

RVl

LT5,6

none

none

Tylenol no. 2 b.i.d.

48

36

3

none

none

Tylenol no. 3 t.i.d.

none

LL3,4

L-I”!

LT9,lO

3

90

LVI

RT7

24

3

LT2,3

R TlQ, Tll

SAT

SAT VIS VAS

VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS

MO U S S U S S U S S U S S U MO/S MO U S S U MO/S MO U

MO/S

MO/S MO U MO/S MO v

MO/S MO U S S U MO MO U

u MO MO u NIL NIL SA

u

S MO

NIL NIL SA MU MO U MO MO U MO MO U

S u

MO

MI u

MO U MO

MO

MO/S S u MI MI SA

S S

MO/S MO U MO MO U MO MO U

MO MO u

u

U MO S

MO MO

MI MI s

MI MI SA MO MO U

MI MO u NIL NIL SA

IC

gOad

severe burning IC

MI MI SA

severe burning IC

severe burning

mild burning

moderate burning and perspiration

severe burning IC

g-d

mild burning gd

mild burning

mild burning

IC

g-l

mild burning

none

none

none

excellent

improved

improved

NR

MI MI SA

MI MI SA MI MI SA

MO MO U MI MO U MI MO U NIL NIL SA

Age

71

80

80

72

69

60

72

60

72

42

Patient

24. EV

2.5. EB

26. HC

21. SD

28. JK

29.NB

30. Go

31.RB

32. GB

33.GH

amittyptyhne 100 mg q.h.s.

I

10

RTl,2

LVl

F

M

F

M

MO

MO U MO MO U

VIS

VAS SAT VIS VAS SAT

164

RT7,8,9

SAT

60

Tylenol t.i.d.

MO/S MO U S S U S S U S S U S S u MO MO U MO MO u S S U

VIS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS SAT VlS VAS SAT VIS VAS SAT VIS VAS SAT VIS VAS

Baseline

-

MO MO U MO MO U S S U MO MO U MO MO u S S U MO MO U NIL NIL S

1

Treatment period (weeks)

RTS

6

Tylenol no. 2 t.i.d.

3

LT6

F

L T9,lO

none

42

RT4,5

F

M

Tylenol 500 mg q.i.d.

30

RT2

F

mg

Demerol50

76

RLl,2

F q.i.d. i.m.

none

24

L vi

Concomitant analgesics

F

Duration PHN (months)

Dermatome

Sex

TABLE I (continued)

MO U MO MO U MO MO U MI MO U NIL NIL S

MO

MO MI U

MO MO U

2

U MO MO U MO MO U MI MI S MI MI S Ml MI S

MO

U MI MI S MO MI U MO

3

MI MI S MI MO S

MO MO U MO MO U MO MO U MI MI S MO MO U S S U

4

good

pleasant warmth after application

none

severe burning especially with perspiration, controlled by Xylocaine

good

Pod

moderate burning helped by Xylocaine

mild burning

severe burning X 2 weeks, then ceased

severe burning controlled by Xylocaine

mild burning in sun only

severe burning controlled by Xylocaine

severe burning

Side effects

NR

NR

good

improved

improved

improved

Response rating

331

Sample and method Thirty-three patients with PI-IN of more than 3 months duration entered this open-label study of 0.025% capsaicin (Zostrix, Genderm Corporation, Northbrook, IL). Twenty-three patients completed the trial. All had moderate to severe pain on a daily basis, unrelieved or poorly controlled by other means. The median duration of PHN was 2 years (range 3 months-14 years, Table I). The entire group consisted of 22 females and 11 males with median age 70 years (range 42-88). A record was kept of analgesic medication taken prophylactically or symptomatically at the onset of and at weekly intervals during the trial. Patients were instructed to apply capsaicin 4 times daily to adequately cover the painful area of skin with as much medication as was necessary for 4 weeks and to return weekly for follow-up assessment. Baseline and weekly assessment was made of the severity of pain by a verbal intensity scale (VIS) of no pain, mild, moderate or severe pain, and by marking a visual analogue scale (VAS) which consisted of a 10 cm line marked ‘no pain’ at one end and ‘pain as bad as it could be’ at the other. The VAS was divided into 3 sections. The first one-third from the ‘no pain’ end was marked ‘mild,’ the middle third ‘moderate’ and the final one-third ‘severe pain.’ The relief of both jabbing and steady burning pain was evaluated at each visit. Pain was also assessed by a daily pain diary dividing the day into 4 segments of 6 h and rating the pain according to a verbal scale as above. Mild pain was considered to be present but not bothersome, moderate pain was disagreeable, bothersome or annoying and severe pain was chosen by the patient if it was unbearable. Disability was rated as absent, mild, moderate or severe. Mild disability did not interfere with activities of daily living (ADL) but impaired ability to perform pleasurable or exertional activities such as sports, moderate disability implied significant interference with ADL and severe disability indicated that the patient was bedridden for most of the day. Patients were asked as a final measure of their status if they were satisfied that pain was under good control. Based on these parameters we determined an excellent result to be no pain at

any time of the day, with full activity, and satisfaction. A good result implied pain that was never worse than mild, mild disability at worst and satisfaction. A fair result was a clearly improved pain status but with moderate pain for part of the day and/or moderate disability and/or a lack of satisfaction with the degree of pain relief. An enquiry was also made as to any untoward effects of capsaicin.

Results (a) Drop-outs

Eleven patients dropped out initially. Nine of these had intolerable burning after application and ceased using capsaicin after from 1 day to 3 weeks because of this. One patient with PHN of 3 months duration had intolerable burning from the ointment combined with a breakdown of the skin into weeping, erythematous small ulcers. One patient had no burning but became frustrated with the lack of pain relief and ceased therapy after 3 weeks. We attempted a second trial in 4 patients with burning by using 5% Xylocaine ointment applied to the skin before capsaicin, covering a smaller area of skin initially and regular oral analgesics. This was successful in 1 patient who then went on to achieve a good result. (b) Effect on pain

Thirteen (39%) of those entering the study achieved at least a good result and 18 (55%) were improved or better. Twenty-three patients completed the full 4 weeks of the trial. Of these 13 (56%) achieved a good (11) or excellent (2) result. If we include the group categorized as ‘improved’ or ‘fair,’ a group which showed significant but unsatisfactory improvement, then the total number with a salutary response was 18 (78%). Eight patients had both jabbing and steady, burning pain, both of which were relieved by treatment. Pain relief most commonly occurred during the first 2 weeks, but the best response was delayed in most until the end of the fourth week (Table II). Five patients had no change in their pain. Two other patients (RB and EB) with no relief after 4 weeks were discovered to be applying the oint-

338 TABLE II

TABLE III

TIMING OF RELIEF

DURATION OF POST-CAPSAICIN BUKNlNCi IN I? PATIENTS COMPLETING THE TRIAL

N=IX. Week

Onset

Best

1

9 s 2 2

0 1 4 13

2 3 4

ment only 2-3 times/day. With re-trial at 4-5 times daily an ‘improved’ and ‘good’ result were obtained. We compared patients responding, not responding and not completing the trial and found

No. of

Week

patients

l

2

3

17

3

2

6

--4 _6

no difference with regard to age, sex, dermatome(s) affected or duration of PHN (P > 0.05 analysis of variance). (c) Post-capsaicin burning (Table Ill) Twenty-six patients experienced a burning sensation after the application of capsaicin oint-

TABLE IV FOLLOW-UP STATUS OF 24 PATIENTS IC = incomplete; NC = no change. Result of trial

One month

Two months

Three months

1. IJ 2. WB 3. MG 4. Jw 5. BC

NC NC IC

NC

NC

NC NC

NC

NC NC

IC

6. BS

excellent

NC recurrence of severe pain off capsaicin good off capsaicin itch a problem recurrence

Patient

7. JL 8. DR 9. AB 10. AC 11. CB 12. MH 13. GC 14. AR 15. JK 16. PS 17. SF 18. MM 19. ps 20. TO 21. ww 22. EM 23. DD 24. EV 25. EB

a=+

27. SD 2a.JK 33. GH

improved good good

IC IC

improved improved improved excellen IC good good IC IC IC good good IC IC improved

recurrence recurrence rwrrence no pain

NC NC

good on nortriptyline

improved on capsaicin good off capsaicin

good on capsaicin

severe severe improved on capsaicin

no pain severe good off capsaicin severe severe

good off capsaicin itch a problem good on capsaicin severe severe improved on capsaicin NC off capsaicin severe pain off capsaicin severe pain off capsaicin no pain off capsaicin severe off caps&in severe off capsaicin good off capsaicin

improved on nortriptyhne recurrence

severe severe (worse) off

capsaicin severe off capsaicin severe off capsaicin severe off capsaicin

.-.---

severe off capsaicin good on capsaicin sewere

good on capsaicin exdlmt off capsaicin severe severe

339

ment. A total of 10 patients initially ceased treatment because of this (9) or burning, combined with skin breakdown (1). Seventeen other patients experienced this after-sensation but were able to complete the trial. Of these 11 patients described the feeling as mild and not disagreeable. In 3 the burning was moderate or disagreeable and in 4 it was severe. The application of 5% Xylocaine ointment before capsaicin enabled 4 patients to tolerate this side effect and complete the trial, although earlier in the trial this method was not used. Three of the 5 patients with no pain relief had no burning sensation after application. In some patients burning ceased with time as the trial progressed. In others it persisted for the full 4 weeks. In no patient was it unbearable by the end of the study. (d)

Effecton sensation

The only sensory change noted was a reduction in hyperaesthesia which always accompanied the subjective observation of the 5 patients who stated that provoked skin sensitivity, such as that induced by clothing contact, was improved or absent. (9) Other analgesics stable I] No change in prophylactic

analgesics such as antidepressant therapy occurred in any patient taking these during the trial. Symptomatic analgesic consumption was reduced or eliminated in all patients demonstrating improved pain status.

Follow-up status was assessed in 28 patients at from 1 to 3 months after the trial’s completion (Table IV). Of 10 patients who did not complete the trial because of severe burning or lack of efficacy, 8 were unchanged and 2 were doing well on nortriptyline. Two patients with no response to capsaicin were unchanged. Twelve patients, who were at least improved at the study’s completion, had recurrence of severe pain when taken off capsaicin. Of these, 4 recaptured the improvement achieved during the trial by re-treatment with capsaicin. Eight of the 12 patients were not retreated because of lack of availability of capsaicin and these remained the same. We were able to assess the timing of recurrence of pain in 10

patients and found this to vary from 3 days to 3 weeks, with a median of 1 week. Four patients had no recurrence of pain while on no therapy. Only one of these had short duration PHN (3 months) prior to treatment, the rest ranged from 24 months to 13 years. Discussion Topical 0.025% capsaicin appears to have an analgesic effect in PHN and a double-bind, placebo-controlled trial is now necessary. The incidence of pain relief found by us is similar to the observations of Bernstein et al. in an uncontrolled study of 12 patients [l], They found that after 4 weeks treatment with caps&in, 3 patients had total relief, 3 were ‘much better,’ 3 were ‘better’ and 3 unchanged. Only 1 instance of an intermittent burning sensation after application was noted. Our results indicate that post-capsaicin burning is a common occurrence resulting in a dropout rate of about one-third of patients entering the trial. This burning sensation may be related to pain relief, as patients with relief all experienced it in varying degrees and 3 of 5 patients who were unchanged did not have it. Perhaps it is indicative of the depletion of substance P and other excitatory peptides. This frequent, untoward effect of capsaicin will make it difficult to blind a placebocontrolled trial unless an active placebo is utilized. The use of topical capsaicin requires supervision and patient education. The following guidelines are recommended: (1) The frequency of application should be 4-5 times daily, as less frequent usage may be less effective. An example of this was the lack of relief by patients RB and EB when application was only twice daily with subsequent better relief at 4 times daily. (2) Treatment should persist for 4 weeks even if relief is not achieved in the first 2 or 3 weeks, as the onset and best response may be delayed until that time. (3) Patients should be instructed to wash the hands after each application in case of inadvertent involvement of the eye by contact. (4) Weekly or bimonthly visits are important to encourage persistence in the face of unresponsive-

340

ness and to monitor and deal with post-capsaicin burning. (5) Severe post-capsaicin burning may become more bearable after the first week or two and may be tolerated by pre-treatment with 5% Xylocaine ointment, by covering smaller skin areas initially and by using an oral analgesic regularly in the first few days. (6) At the end of 4 weeks treatment may be withdrawn and re-instituted if there is the recurrence of pain. The duration of treatment for most patients has not been established and could be prolonged. Acknowledgement Capsaicin 0.025% (Zostrix) was generously supplied by the Genderm coloration of Northbrook, IL, U.S.A.

2 Burgeon, C.F., Burgoon, J.S. and Baldridge, Ci.11.. I he natural history of herpes zoster, JAMA, 164 (1957) 265..-269 3 Demoragas, J.M. and Kierland, R.R., The outcome of patients with herpes zoster, Arch. Dermatol., 75 tl957) 193-196. 4 Isaacs, G., Permanent local anesthesia and anhidrosis after clove oil spillage, Lancet, i (1933) 882. A. and Szolcsanyi, 3.. Direct 5 Jansco, N., Jr&o-Gabor, evidence for neurogenic infIammation and its prevention by denervation and by pretreatment with capsaicin. Br. J. Pharmacol., 31 (1967) 138-151. 6 Jansco, G., Kiraly, E. and Jansco-Gabor. A.. Pharmacologically induced selective degeneration of chemo~nsit~ve primary sensory neurons, Nature. 270 (1977) 741-743. I Jessell, T.M., Iversen, L.L. and Cueho, A.C., Capsaicin-induced depletion of substance P from primary sensory naurones, Brain Res., 152 (1978) 132-188. 8 Otsuka, M. and Konski, S., Release of substance P-lie immunoreactivity from isolated spinal cord of newborn rat, Nature, 164 (1976) 83. 9 Turnbull, A., Tincture of Capsicum as a Remedy for Chillblains and Toothache, Dublin Med. Press, 1850, pp. 95-96. 10 Watson, P.N. and Evans, R.J., Treatment of postherpetic neuralgia,

11 Watson, versus

References 1 Bernstein, J.E., Bickers, DR., Dahl, M.V. and Roshal, J.Y., Treatment of chronic postherpetic neuralgia with topical capsaicin, 3. Am. Acad. Dermatol., 17 (1987) 93-96.

J. Neuropharmacol., 9 (1986) 533-541. C.P., Evans, R.J.. Reed, K. et al., Amitriptyline placebo in postherpetic neuralgia, Neurology, 32

(1982) 670-673. 12 Yaksh, T.L., Farb, D.H., Leeman, SE. and Jesseli, T.M., Intrathecal capsaicin depletes substance P in the rat spinal cord and produces prolonged thermal analgesia, Science, 206 (1979) 481-483.

Editor’s note In this interesting clinical note, the authors have applied 0.025% capsaicin repeatedly and the patients report a burning sensation on each application and a relatively rapid return of their pain after the cessation of therapy. The reader should beware that most of the cited literature deals with very much higher concentrations. The originator, N. Jansco, used 1% capsaicin. At these concentrations, capsaicin is a neurotoxin and produces block or destruction (reviewed in Fitzgerald [2]). It may therefore increase the effect of deafferentation. High concentration caps&in on peripheral nerve in rat produces decreased inhibition and enlarged receptive fields in spinal cord 131; 1% topical caps&in in man produces thermal hype&e&i (11. The basis of the effect reported here, if validated in a controlled study, is presumably the

generation of central inhibition by prolonged afferent barrages, fighting fire with fire. The reason for this note is to warn that higher concentrations are likely to produce different and possibly deleterious effects. P.D. Wall

References S. and Lynn, B.. Abolition of axon reflex flare in human skin by c&&in, J. Physiol. (Loud.), 310 (1981)

1 Carpenter, 69P-7OP. 2 FitzgazU,

M., Caps&in and sensory netnones - a review, Pain, 15 (1983) 109-139. 3 Wall, P.D., Fitzgerald. M. and Wodf, C.J.. Effects of capaaicinonreceptivelieldaandoninhibitiatsinratspinal cord, Exp. Net&., 78 (1982) 425-436.