Pain, 51 (1992) 375-379 0 1992 Elsevier Science
375 Publishers
B.V. All rights reserved
0304-3959/92/$05.00
PAIN 02185
The postmastectomy
pain syndrome and topical capsaicin: a randomized trial
C. Peter N. Watson and Ramon J. Evans The Irene Eleanor Smythe Pain Clinic, Toronto General Hospital Toronto, Ontario M5G 2C4 (Canada) (Received
28 April 1992, revision
received
10 August
1992, accepted
13 August
1992)
Summary This paper describes a randomized parallel trial of topical 0.075% capsaicin versus vehicle (placebo) in the postmastectomy pain syndrome (PMPS). The study was double-blind in design; however, this was compromised by the burning sensation induced by capsaicin. We could not demonstrate a significant difference in the visual analogue scale (VAS) for steady pain although a trend was present. A significant difference was found, however, in the VAS for jabbing pain, in category pain severity scales, and in overall pain relief scales in favour of capsaicin. Five of 13 patients on capsaicin were categorized as good-to-excellent responses with 8 (62%) having 50% or greater improvement. Only 1 of 10 cases had a good response to vehicle with 3 rated as 50% or better. Key words: Postmastectomy
pain syndrome; Topical capsaicin
capsaicin is more effective than a vehicle ointment in PMPS.
Introduction
The postmastectomy pain syndrome (PMPS) is thought to be due to injury to the intercostobrachial nerve (ICBN) at the time of surgery (Assa 1974; Foley 1978; Wood 1978; Granek et al. 1984). One study suggested that involvement of that nerve alone did not account for most cases (Watson et al. 1989). PMPS affects a small percentage of individuals and occurs after lumpectomy as well as more radical procedures. The natural history is unclear, and some patients prove to be difficult, if not intractable, management problems despite various approaches. An uncontrolled, nonblinded trial indicated that topical capsaicin appeared to be helpful in this condition (Watson et al. 1989). A previous open-label trial of topical capsaicin in another neuropathic pain syndrome, postherpetic neuralgia, had shown promise (Watson 1988). However, a vehicle (placebo)-controlled parallel trial in 53 patients failed to show a significant difference (unpublished data), illustrating the importance of this latter type of trial with this approach. This study is a randomized, parallel, attempted double-blind trial to determine if topical
Correspondence Suite 303, Toronto,
to: C. Peter N. Watson, 3101 Bloor Street Ontario M8X 2W2, Canada.
West,
Methods This protocol with informed consent was approved Committee of the Toronto General Hospital.
by the Ethics
Subjects Patients were obtained from spontaneous referrals to our pain clinic and from advertisements and articles in the medical and lay press. Criteria for this diagnosis were: (1) pain in the anterior chest wall, and/or axilla and/or medial upper arm; (2) pain persisting for more than 3 months after mastectomy; (3) loss of sensation and/or increased responsiveness of the skin in the painful areas to a tactile stimulus (hyperesthesia, dysesthesia, allodynia); and (4) absence of recurrent malignant disease. Patients could continue with previous analgesics as needed and these were recorded weekly. Inclusion criteria in addition to the above were (1) pain of at least moderate severity (disagreeable. unpleasant, uncomfortable) for at least onehalf the day (12 or more hours); (2) no evidence of impaired ability to attend weekly visits and communicate in order to deal with outcome measures; (3) no topical agent used for 7 days prior to trial onset; and (4) no new oral agent to be used during the trial. Patients were excluded if (1) open skin lesions were present in the area of pain; (2) other skin conditions were present in the affected area; (3) severe depression with voiced suicidal intent was present; and (4) another unrelated significant pain problem existed. The sample size of 25 was selected based on our previous experience with an open-label trial of
I
Age
1 Yr
10 mo 1.5 yr
7.5 yr
5 mo 6 mo
67 5.5
58
43 48
SA AJ
HAG Drop-outs WE 02
+
-I-
+ + +
+ -t i-
95 54
83 35 5h 57 50
+ + + + +
S.E.
-
48 55 40
5S
49 30
64 72 66
100 100 55
46 87 x4 0 JO 88 0 74 57 62 60 90 0 0
-
50
62 50
hh 66 82
75 100 50
error for improvement
13 10
Jabbing CAPS PLAC
for steady
61.4 49.2
59.9 60.0
9.24 8.44
4.74 5.13
I2 10
12 10
TRIAL
53 55
54
82 30
92 72 58
0 100 0
-
0 0
49 il
80 0 60 0
40 0 58 0 78 0
880 100 0 0 0
0 0 92 0 SO 0 0 YO 25 0 24 0 34 0 140 47 0 40 0 20 0 45 0 26 0 Excell. Good Good Good Good > 50% > 50% > 50% < 50% < 5070 < 50% Good > 50% > 50%
Global rating
- 33.8 - 0.3
- 17.x - 9.6
-
Refused
Good 2550%, > 50-75%, > 75-100%). A VAS for pain relief was also marked. Depression was rated by the Beck Depression Inventory (BDI) (Beck et al. 1961; Beck and Beamesderfer 19741,with a score of 9 or less as no depression, lo-15 as mild, 16-19 as mild/moderate, 20-29 as moderate/severe, and 30-63 as severe depression. Areas of sensory loss or reduction were marked on the skin according to examination by pinprick, but the response to light touch was also assessed within the area demarcated, and a judgement made as to whether there was a reduction in that modality as well. Hyperesthesia, dysesthesia and allodynia were tested by stroking the skin lightly with a cotton-tipped stick and by gentle traction between thumb and forefinger. If these stimuli resulted in a sensation of increased sensitivity when compared to the corresponding control area of the other side of the body, the response was categorized as hyperesthesia. If the sensation was disagreeable it was documented as dysesthesia and if painful as allodynia. The definition of these terms was in keeping with the taxonomy published by Merskey (1979). Baseline and weekly evaluations were made of pain severity (VIS and VAS), pain relief, disability, degree of satisfaction with pain relief and percentage improvement. Pain was also monitored with a daily pain diary. dividing the day into four 6-h segments and rating the pain according to a verbal scale as above. 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 part or most of the day. Patients were asked as a final measure of their status if they were satisfied that pain was under good control. An enquiry was also made of any untoward effects of capsaicin. Based on these parameters. we determined that an ‘excellent’ response to this treatment was no pain at any time of the day, with full activity, no side effects and satisfaction. A ‘good’ result implied that pain was never worse than mild, mild disability at worst, mild but tolerable side effects and satisfaction with treatment. A ‘fair’ result was clearly improved pain status (by at least 50% according to the VAS and patient’s estimate of percentage improvement) 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. A ‘poor’ response consisted of some amelioration (less than 5O%c),moderate pain and disability, and dissatisfaction.
Data analysis The analyses of VAS scores for steady, jabbing and skin pain and pain relief were made for each treatment using a paired t test for
differences between baseline and week 6. A 2-sample t test of the above difference was used to compare the effect of capsaicin and vehicle control for each quality of pain and for pain relief. A comparison of category scales for pain and effectiveness was made by Fisher’s exact test.
Results
Twenty-five patients entered,the trial (Table I). Two patients did not complete the 1st period: one because of the recurrence of malignancy at a remote site and the other because of burning induced by capsaicin. Age and initial treatment
The median age of patients was 58 years (range: 36-78). Of the 25 patients, 17 had undergone modified radical mastectomies, 5 had had lumpectomies, 3 of those with axillary dissection, 1 had a radical mastectomy, and 2 simple mastectomies. Pain duration, onset, site and intensity
The median pain duration was 4 years (range: 5 months to 16 years). The interval between surgery and pain onset was immediate in 20 patients and from 1 to 4 weeks in 5 patients. The chief pain site was a combination of anterior chest and upper arm in 16, arm alone in 6 and anterior chest alone in 3 patients. According to category and VAS scales, pain was moderate in 15 and severe in 10 cases. Sensory examination
All patients exhibited an abnormal sensory examination, most having a combination of sensory loss and allodynia. In addition to these findings, 1 patient had hyperalgesia and 2 painful responses were hyperpathic. One patient had only sensory loss. Although 6 patients had pain confined to the ICBN, no patient had sensory findings confined to this nerve. The majority of patients (16) had allodynia and/or sensory loss involving both ICBN and intercostal nerve (ICN) territories. Six patients had sensory findings confined to the area of ICNs alone. We were not able to demonstrate a significant difference in allodynia and sensory loss before and after treatment between vehicle and capsaicin. Assessment of mood
Of 20 patients for whom BDIs were obtained, 9 were not depressed, 9 were mildly depressed, 1 was moderately and 1 severely depressed.
Treatment
results
Pain
With VAS scales for steady pain, a significant change from baseline to week 6 was seen with capsaicin (P =
37x TABLE
II
CHANGE IN CATEGORY SCALES FROM SEVERE ERATE PAIN FOR CAPSAICIN vs. VEHICLE
OR MOD-
Capsaicin
exact
appears
to be better
than
vehicle
(Fisher’s
test)
( P = 0.011. Change
Treatment
to
No pain
Mild
Moderate
No change
Capsaicin (n=131
4
z
3
4
Vehicle tn=lOl
0
1
0
Y
Sensory findings We were not able to demonstrate any significant difference in sensory findings between the 2 groups before and after treatment or between responders and non-responders.
0.03) but not vehicle (P = 0.25). However, we were unable to demonstrate a significant difference between capsaicin and vehicle (P = 0.40) but concluded that a trend was present and that a larger number of patients might have demonstrated significance. VAS for jabbing pain showed a change from baseline to week 6 with capsaicin (P = 0.001) but not with vehicle (P = 0.981 and a significant difference when both treatments were compared (P < 0.05). For skin pain (pain on tactile skin contact) the VAS showed no significant change from baseline to week 6 and no difference between both treatments. VAS for pain relief showed a significant change with capsaicin (P = 0.0004) but not with vehicle CP = 0.06) and a significant difference between both treatments in favour of capsaicin (P = 0.04). According to category scales and diaries (Table II), 9 of 13 patients with capsaicin had a change to an improved category versus only 1 of 10 with vehicle (Fisher’s exact test) (P = 0.01). Of these, 6 of 13 patients had mild or no pain with capsaicin versus 1 case with mild pain with vehicle. Global ratings (Table III) which took into account pain, pain relief, disabling side effects and level of satisfaction revealed that 8 of 13 patients (62%) achieved 50% or greater improvement, 5 of whom had good-to-excellent responses. Three of 10 patients (30%)
TABLE
III
GLOBAL RATINGS OF FINAL PAIN STATUS COMPARING CAPSAICIN AND VEHICLE TAKING INTO ACCOUNT VERBAL INTENSITY RATINGS, PAIN RELIEF. SIDE EFFECTS AND SATISFACTION RATING Capsaicin appears ( P = 0.0071. Treatment
Capsaicin tn=131 Vehicle tn=lOl
more
Excellent
effective
than
vehicle
Good
Poor results but improved
(Fisher’s
> 50%
< 50%
on vehicle were 50% better and only 1 gave a good response. The difference between those improved with capsaicin and with vehicle was statistically significant (Fisher’s exact test) (P = 0.007). We were not able to determine any difference between patients on placebo and capsaicin or between responders and non-responders with regard to patient characteristics.
exact
test)
Adcqerse effects Twelve of 13 patients completing treatment with capsaicin had a burning sensation from the ointment and 1 stopped the trial because of it. Two patients found the sensation to be pleasant, 6 described the burning as severe but bearable, 4 described burning as mild or moderate and bearable, and 1 experienced sneezing and coughing after use. Only 1 patient on vehicle described severe burning but said she was not sure if it was the ointment or underlying pain from PMPS. Effect on disability, satisfaction, and concomitant analgesic used Ten of 13 patients on capsaicin experienced a lessening of disability; in 5 patients this was a change from moderate or severe to mild. Three patients on vehicle thought they were less disabled. Six of 13 patients expressed satisfaction with the degree of pain relief and tolerability of side effects with capsaicin versus 1 of 10 with vehicle. Ten patients on capsaicin used less analgesics as needed versus 1 with vehicle. Follow-up We were able to obtain follow-up results on 21 patients from 10 months to 2.5 years after completion of the trial. All patients, except the 2 dropouts, had been treated with capsaicin either during or following completion of the trial. Of these, 2 patients had no pain with 1 using capsaicin; 14 were good results. One patient with no pain and 2 with good results were on capsaicin; the remaining cases used no treatment. One patient had died and 4 were unchanged.
No change
Discussion
I
4
3
3
2
0
I
2
0
7
Topical 0.075%~ capsaicin more effective than the vehicle for the relief of PMPS. All our ing pain (> 5 months), and
cream appeared to be cream used in this trial patients had longstandvarious treatments had
379
TABLE
IV
GUIDELINES
FOR
THE USE OF TOPICAL
CAPSAICIN
should be 4-5 times a day as less 1. The frequency of application frequent use may be less effective. should persist for 4-6 weeks even if relief is not 2. Treatment achieved in the first 2 or 3 weeks, as the onset and best response may be delayed until that time. should be instructed to wash their hands after each 3. Patients application in case of inadvertent involvement of the eye by contact. 4. Weekly or bimonthly visits are important to encourage compliance and to deal with post-capsaicin burning if it occurs. pain occurs it may become more bearable 5. If severe post-capsaicin after the 1st or 2nd week and may be tolerated by pretreatment with 5% lidocaine ointment, by covering smaller skin areas initially and by using an oral analgesic regularly in the first few days. may be withdrawn and 6. At the end of 4-5 weeks treatment re-instituted if there is recurrence of pain. The duration of treatment for most patients has not been established and could be prolonged.
been unsuccessful. Relief of paroxysmal jabbing pain was most prominent by VAS, with a trend towards relief of steady pain and no effect on pain induced by tactile contact with the skin. Category scales indicated that 6 of 13 (38%) had mild or no pain on treatment versus 1 (10%) with vehicle, and 46% receiving capsaicin were satisfied with the degree of relief and side effects versus only 1 of 10 (10%) on vehicle. A burning sensation induced by capsaicin was frequent and guidelines for dealing with it and for the use of capsaicin are presented in Table IV. As in our previous open-label trial of this agent (Watson et al. 1989), none of these patients had sensory findings confined to ICBN territory, but rather sensory loss and/or allodynia implied involvement of other ICNs. Most of our patients were either not depressed or only mildly so, thus arguing against a major affective disorder of this nature playing a role in the pain. We were unable to demonstrate any significant difference in sensory loss or allodynia before and after treatment with the methods used which, however, were non-quantitative and may have been too insensitive. The presence of burning induced by capsaicin was
present in all but 1 patient and in only 1 patient on vehicle. This threatens the double-blind nature of the trial and dealing with this issue is problematic for future controlled trials of this agent. We encountered, however, a similar result with increased burning in the capsaicin but not vehicle group in a blinded, controlled, parallel trial in 53 cases of postherpetic neuralgia in which no difference or trend was found between the 2 treatments (unpublished data). It is impossible to say whether the good follow-up results were an effect of treatment or due to a natural history effect. We conclude that topical capsaicin is more effective than vehicle and, in some patients with this otherwise intractable disorder, satisfactory relief can be obtained which may persist for an extended period.
Acknowledgement
Capsaicin 0.075% (Zostrix-HP) was generously supplied by the Genderm Corporation (Lincolnshire, IL, USA). Mrs. Angela Baird was invaluable in typing the manuscript and preparing the tables.
References Assa, J., The intercostobrachial nerve in radical mastectomy, J. Surg. Oncol.. 6 (1974) 123-126. Beck, A.T. and Beamesderfer, A., Assessment of depression, Mod. Probl. Pharmacopsychiat., 4 (1974) 151-169. Beck, A.T., Mendelson, M., Mack, J.E. and Erbaugh, J.K., Inventory for measuring depression, Arch. Gen. Psychiat., 4 (1961) 561-571. Foley, K.M., Pain syndromes in patients with cancer, Med. Clin. N. Am., 71 (1978) 177-178. Granek. I., Ashikari, R. and Foley, K.M., The postmastectomy pain syndrome: clinical and anatomical correlates, Proc. ASCO, 3 (1984) 122. Merskey, H.. Pain terms: a list with definitions and notes on usage. Recommended by the IASP subcommittee on taxonomy, Pain, 6 (1979) 249-252. Watson, C.P.N.. Evans, R.J. and Watt, V.R., Postherpetic neuralgia and topical capsaicin, Pain. 33 (1988) 333-340. Watson, C.P.N.. Evans, R.J. and Watt, V.R., The postmastectomy pain syndrome and the effect of topical capsaicin, Pain, 38 (1989) 177-186. Wood, K.M., Intercostobrachial nerve entrapment syndrome, Sth Med. J.. 71 (1978) 662-663.
375 Publishers
B.V. All rights reserved
0304-3959/92/$05.00
PAIN 02185
The postmastectomy
pain syndrome and topical capsaicin: a randomized trial
C. Peter N. Watson and Ramon J. Evans The Irene Eleanor Smythe Pain Clinic, Toronto General Hospital Toronto, Ontario M5G 2C4 (Canada) (Received
28 April 1992, revision
received
10 August
1992, accepted
13 August
1992)
Summary This paper describes a randomized parallel trial of topical 0.075% capsaicin versus vehicle (placebo) in the postmastectomy pain syndrome (PMPS). The study was double-blind in design; however, this was compromised by the burning sensation induced by capsaicin. We could not demonstrate a significant difference in the visual analogue scale (VAS) for steady pain although a trend was present. A significant difference was found, however, in the VAS for jabbing pain, in category pain severity scales, and in overall pain relief scales in favour of capsaicin. Five of 13 patients on capsaicin were categorized as good-to-excellent responses with 8 (62%) having 50% or greater improvement. Only 1 of 10 cases had a good response to vehicle with 3 rated as 50% or better. Key words: Postmastectomy
pain syndrome; Topical capsaicin
capsaicin is more effective than a vehicle ointment in PMPS.
Introduction
The postmastectomy pain syndrome (PMPS) is thought to be due to injury to the intercostobrachial nerve (ICBN) at the time of surgery (Assa 1974; Foley 1978; Wood 1978; Granek et al. 1984). One study suggested that involvement of that nerve alone did not account for most cases (Watson et al. 1989). PMPS affects a small percentage of individuals and occurs after lumpectomy as well as more radical procedures. The natural history is unclear, and some patients prove to be difficult, if not intractable, management problems despite various approaches. An uncontrolled, nonblinded trial indicated that topical capsaicin appeared to be helpful in this condition (Watson et al. 1989). A previous open-label trial of topical capsaicin in another neuropathic pain syndrome, postherpetic neuralgia, had shown promise (Watson 1988). However, a vehicle (placebo)-controlled parallel trial in 53 patients failed to show a significant difference (unpublished data), illustrating the importance of this latter type of trial with this approach. This study is a randomized, parallel, attempted double-blind trial to determine if topical
Correspondence Suite 303, Toronto,
to: C. Peter N. Watson, 3101 Bloor Street Ontario M8X 2W2, Canada.
West,
Methods This protocol with informed consent was approved Committee of the Toronto General Hospital.
by the Ethics
Subjects Patients were obtained from spontaneous referrals to our pain clinic and from advertisements and articles in the medical and lay press. Criteria for this diagnosis were: (1) pain in the anterior chest wall, and/or axilla and/or medial upper arm; (2) pain persisting for more than 3 months after mastectomy; (3) loss of sensation and/or increased responsiveness of the skin in the painful areas to a tactile stimulus (hyperesthesia, dysesthesia, allodynia); and (4) absence of recurrent malignant disease. Patients could continue with previous analgesics as needed and these were recorded weekly. Inclusion criteria in addition to the above were (1) pain of at least moderate severity (disagreeable. unpleasant, uncomfortable) for at least onehalf the day (12 or more hours); (2) no evidence of impaired ability to attend weekly visits and communicate in order to deal with outcome measures; (3) no topical agent used for 7 days prior to trial onset; and (4) no new oral agent to be used during the trial. Patients were excluded if (1) open skin lesions were present in the area of pain; (2) other skin conditions were present in the affected area; (3) severe depression with voiced suicidal intent was present; and (4) another unrelated significant pain problem existed. The sample size of 25 was selected based on our previous experience with an open-label trial of
I
Age
1 Yr
10 mo 1.5 yr
7.5 yr
5 mo 6 mo
67 5.5
58
43 48
SA AJ
HAG Drop-outs WE 02
+
-I-
+ + +
+ -t i-
95 54
83 35 5h 57 50
+ + + + +
S.E.
-
48 55 40
5S
49 30
64 72 66
100 100 55
46 87 x4 0 JO 88 0 74 57 62 60 90 0 0
-
50
62 50
hh 66 82
75 100 50
error for improvement
13 10
Jabbing CAPS PLAC
for steady
61.4 49.2
59.9 60.0
9.24 8.44
4.74 5.13
I2 10
12 10
TRIAL
53 55
54
82 30
92 72 58
0 100 0
-
0 0
49 il
80 0 60 0
40 0 58 0 78 0
880 100 0 0 0
0 0 92 0 SO 0 0 YO 25 0 24 0 34 0 140 47 0 40 0 20 0 45 0 26 0 Excell. Good Good Good Good > 50% > 50% > 50% < 50% < 5070 < 50% Good > 50% > 50%
Global rating
- 33.8 - 0.3
- 17.x - 9.6
-
Refused
Good 2550%, > 50-75%, > 75-100%). A VAS for pain relief was also marked. Depression was rated by the Beck Depression Inventory (BDI) (Beck et al. 1961; Beck and Beamesderfer 19741,with a score of 9 or less as no depression, lo-15 as mild, 16-19 as mild/moderate, 20-29 as moderate/severe, and 30-63 as severe depression. Areas of sensory loss or reduction were marked on the skin according to examination by pinprick, but the response to light touch was also assessed within the area demarcated, and a judgement made as to whether there was a reduction in that modality as well. Hyperesthesia, dysesthesia and allodynia were tested by stroking the skin lightly with a cotton-tipped stick and by gentle traction between thumb and forefinger. If these stimuli resulted in a sensation of increased sensitivity when compared to the corresponding control area of the other side of the body, the response was categorized as hyperesthesia. If the sensation was disagreeable it was documented as dysesthesia and if painful as allodynia. The definition of these terms was in keeping with the taxonomy published by Merskey (1979). Baseline and weekly evaluations were made of pain severity (VIS and VAS), pain relief, disability, degree of satisfaction with pain relief and percentage improvement. Pain was also monitored with a daily pain diary. dividing the day into four 6-h segments and rating the pain according to a verbal scale as above. 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 part or most of the day. Patients were asked as a final measure of their status if they were satisfied that pain was under good control. An enquiry was also made of any untoward effects of capsaicin. Based on these parameters. we determined that an ‘excellent’ response to this treatment was no pain at any time of the day, with full activity, no side effects and satisfaction. A ‘good’ result implied that pain was never worse than mild, mild disability at worst, mild but tolerable side effects and satisfaction with treatment. A ‘fair’ result was clearly improved pain status (by at least 50% according to the VAS and patient’s estimate of percentage improvement) 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. A ‘poor’ response consisted of some amelioration (less than 5O%c),moderate pain and disability, and dissatisfaction.
Data analysis The analyses of VAS scores for steady, jabbing and skin pain and pain relief were made for each treatment using a paired t test for
differences between baseline and week 6. A 2-sample t test of the above difference was used to compare the effect of capsaicin and vehicle control for each quality of pain and for pain relief. A comparison of category scales for pain and effectiveness was made by Fisher’s exact test.
Results
Twenty-five patients entered,the trial (Table I). Two patients did not complete the 1st period: one because of the recurrence of malignancy at a remote site and the other because of burning induced by capsaicin. Age and initial treatment
The median age of patients was 58 years (range: 36-78). Of the 25 patients, 17 had undergone modified radical mastectomies, 5 had had lumpectomies, 3 of those with axillary dissection, 1 had a radical mastectomy, and 2 simple mastectomies. Pain duration, onset, site and intensity
The median pain duration was 4 years (range: 5 months to 16 years). The interval between surgery and pain onset was immediate in 20 patients and from 1 to 4 weeks in 5 patients. The chief pain site was a combination of anterior chest and upper arm in 16, arm alone in 6 and anterior chest alone in 3 patients. According to category and VAS scales, pain was moderate in 15 and severe in 10 cases. Sensory examination
All patients exhibited an abnormal sensory examination, most having a combination of sensory loss and allodynia. In addition to these findings, 1 patient had hyperalgesia and 2 painful responses were hyperpathic. One patient had only sensory loss. Although 6 patients had pain confined to the ICBN, no patient had sensory findings confined to this nerve. The majority of patients (16) had allodynia and/or sensory loss involving both ICBN and intercostal nerve (ICN) territories. Six patients had sensory findings confined to the area of ICNs alone. We were not able to demonstrate a significant difference in allodynia and sensory loss before and after treatment between vehicle and capsaicin. Assessment of mood
Of 20 patients for whom BDIs were obtained, 9 were not depressed, 9 were mildly depressed, 1 was moderately and 1 severely depressed.
Treatment
results
Pain
With VAS scales for steady pain, a significant change from baseline to week 6 was seen with capsaicin (P =
37x TABLE
II
CHANGE IN CATEGORY SCALES FROM SEVERE ERATE PAIN FOR CAPSAICIN vs. VEHICLE
OR MOD-
Capsaicin
exact
appears
to be better
than
vehicle
(Fisher’s
test)
( P = 0.011. Change
Treatment
to
No pain
Mild
Moderate
No change
Capsaicin (n=131
4
z
3
4
Vehicle tn=lOl
0
1
0
Y
Sensory findings We were not able to demonstrate any significant difference in sensory findings between the 2 groups before and after treatment or between responders and non-responders.
0.03) but not vehicle (P = 0.25). However, we were unable to demonstrate a significant difference between capsaicin and vehicle (P = 0.40) but concluded that a trend was present and that a larger number of patients might have demonstrated significance. VAS for jabbing pain showed a change from baseline to week 6 with capsaicin (P = 0.001) but not with vehicle (P = 0.981 and a significant difference when both treatments were compared (P < 0.05). For skin pain (pain on tactile skin contact) the VAS showed no significant change from baseline to week 6 and no difference between both treatments. VAS for pain relief showed a significant change with capsaicin (P = 0.0004) but not with vehicle CP = 0.06) and a significant difference between both treatments in favour of capsaicin (P = 0.04). According to category scales and diaries (Table II), 9 of 13 patients with capsaicin had a change to an improved category versus only 1 of 10 with vehicle (Fisher’s exact test) (P = 0.01). Of these, 6 of 13 patients had mild or no pain with capsaicin versus 1 case with mild pain with vehicle. Global ratings (Table III) which took into account pain, pain relief, disabling side effects and level of satisfaction revealed that 8 of 13 patients (62%) achieved 50% or greater improvement, 5 of whom had good-to-excellent responses. Three of 10 patients (30%)
TABLE
III
GLOBAL RATINGS OF FINAL PAIN STATUS COMPARING CAPSAICIN AND VEHICLE TAKING INTO ACCOUNT VERBAL INTENSITY RATINGS, PAIN RELIEF. SIDE EFFECTS AND SATISFACTION RATING Capsaicin appears ( P = 0.0071. Treatment
Capsaicin tn=131 Vehicle tn=lOl
more
Excellent
effective
than
vehicle
Good
Poor results but improved
(Fisher’s
> 50%
< 50%
on vehicle were 50% better and only 1 gave a good response. The difference between those improved with capsaicin and with vehicle was statistically significant (Fisher’s exact test) (P = 0.007). We were not able to determine any difference between patients on placebo and capsaicin or between responders and non-responders with regard to patient characteristics.
exact
test)
Adcqerse effects Twelve of 13 patients completing treatment with capsaicin had a burning sensation from the ointment and 1 stopped the trial because of it. Two patients found the sensation to be pleasant, 6 described the burning as severe but bearable, 4 described burning as mild or moderate and bearable, and 1 experienced sneezing and coughing after use. Only 1 patient on vehicle described severe burning but said she was not sure if it was the ointment or underlying pain from PMPS. Effect on disability, satisfaction, and concomitant analgesic used Ten of 13 patients on capsaicin experienced a lessening of disability; in 5 patients this was a change from moderate or severe to mild. Three patients on vehicle thought they were less disabled. Six of 13 patients expressed satisfaction with the degree of pain relief and tolerability of side effects with capsaicin versus 1 of 10 with vehicle. Ten patients on capsaicin used less analgesics as needed versus 1 with vehicle. Follow-up We were able to obtain follow-up results on 21 patients from 10 months to 2.5 years after completion of the trial. All patients, except the 2 dropouts, had been treated with capsaicin either during or following completion of the trial. Of these, 2 patients had no pain with 1 using capsaicin; 14 were good results. One patient with no pain and 2 with good results were on capsaicin; the remaining cases used no treatment. One patient had died and 4 were unchanged.
No change
Discussion
I
4
3
3
2
0
I
2
0
7
Topical 0.075%~ capsaicin more effective than the vehicle for the relief of PMPS. All our ing pain (> 5 months), and
cream appeared to be cream used in this trial patients had longstandvarious treatments had
379
TABLE
IV
GUIDELINES
FOR
THE USE OF TOPICAL
CAPSAICIN
should be 4-5 times a day as less 1. The frequency of application frequent use may be less effective. should persist for 4-6 weeks even if relief is not 2. Treatment achieved in the first 2 or 3 weeks, as the onset and best response may be delayed until that time. should be instructed to wash their hands after each 3. Patients application in case of inadvertent involvement of the eye by contact. 4. Weekly or bimonthly visits are important to encourage compliance and to deal with post-capsaicin burning if it occurs. pain occurs it may become more bearable 5. If severe post-capsaicin after the 1st or 2nd week and may be tolerated by pretreatment with 5% lidocaine ointment, by covering smaller skin areas initially and by using an oral analgesic regularly in the first few days. may be withdrawn and 6. At the end of 4-5 weeks treatment re-instituted if there is recurrence of pain. The duration of treatment for most patients has not been established and could be prolonged.
been unsuccessful. Relief of paroxysmal jabbing pain was most prominent by VAS, with a trend towards relief of steady pain and no effect on pain induced by tactile contact with the skin. Category scales indicated that 6 of 13 (38%) had mild or no pain on treatment versus 1 (10%) with vehicle, and 46% receiving capsaicin were satisfied with the degree of relief and side effects versus only 1 of 10 (10%) on vehicle. A burning sensation induced by capsaicin was frequent and guidelines for dealing with it and for the use of capsaicin are presented in Table IV. As in our previous open-label trial of this agent (Watson et al. 1989), none of these patients had sensory findings confined to ICBN territory, but rather sensory loss and/or allodynia implied involvement of other ICNs. Most of our patients were either not depressed or only mildly so, thus arguing against a major affective disorder of this nature playing a role in the pain. We were unable to demonstrate any significant difference in sensory loss or allodynia before and after treatment with the methods used which, however, were non-quantitative and may have been too insensitive. The presence of burning induced by capsaicin was
present in all but 1 patient and in only 1 patient on vehicle. This threatens the double-blind nature of the trial and dealing with this issue is problematic for future controlled trials of this agent. We encountered, however, a similar result with increased burning in the capsaicin but not vehicle group in a blinded, controlled, parallel trial in 53 cases of postherpetic neuralgia in which no difference or trend was found between the 2 treatments (unpublished data). It is impossible to say whether the good follow-up results were an effect of treatment or due to a natural history effect. We conclude that topical capsaicin is more effective than vehicle and, in some patients with this otherwise intractable disorder, satisfactory relief can be obtained which may persist for an extended period.
Acknowledgement
Capsaicin 0.075% (Zostrix-HP) was generously supplied by the Genderm Corporation (Lincolnshire, IL, USA). Mrs. Angela Baird was invaluable in typing the manuscript and preparing the tables.
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