Download A randomized, double-blind, placebo

Research Paper
A randomized, double-blind, placebo-controlled
trial of injected capsaicin for pain in
Morton’s neuroma
Claudia M. Campbella,*, Eric Diamondb, William K. Schmidtc, Margaret Kellyc, Robert Allenc, William Houghtond,
Kerrie L. Bradyc, James N. Campbellc,e
Abstract
Intermetatarsal neuroma or Morton’s neuroma is a painful condition of the foot resulting from an entrapment of the common digital
nerve typically in the third intermetatarsal space. The pain can be severe and especially problematic with walking. Treatment options
are limited and surgery may lead to permanent numbness in the toes. Capsaicin, the pungent ingredient of hot peppers, produces
analgesia by inducing retraction of nociceptive afferents from the area of innervation and is effective in treating certain neuropathic
pain disorders. A randomized double-blind placebo-controlled study was conducted to test the efficacy, tolerability, and safety of
a single 0.1 mg dose of capsaicin vs placebo injected into the region of the neuroma. A total of 58 subjects diagnosed with Morton’s
neuroma with foot pain $4 (0-10 numerical pain rating scale) were injected with 2 mL of lidocaine into the intermetatarsal space
proximal to the neuroma to provide local anesthesia. After 5 minutes, 0.1 mg capsaicin or placebo was injected into the
intermetatarsal space containing the painful neuroma. Average foot pain was rated for 2 weeks before through 4 weeks after
injection. At weeks 1 and 4, the decrease in pain was significantly greater in the subjects treated with capsaicin (P 5 0.021 and
P 5 0.019, respectively). A trend toward significance was noted at weeks 2 and 3. Improvements in functional interference scores
and reductions in oral analgesic use were also seen in the capsaicin-treated group. These findings suggest that injection of capsaicin
is an efficacious treatment option for patients with painful intermetatarsal neuroma.
Keywords: Capsaicin, Morton’s neuroma, Intermetatarsal neuroma, Pain, Clinical trial
1. Introduction
Morton’s neuroma refers to a painful condition of the foot
associated with a localized enlargement of the common digital
nerve located in the third intermetatarsal space. Symptoms
consist of pain, tenderness, paresthesias, and often a sense of
numbness in an area corresponding to the location of the
neuroma and its area of innervation on the third and fourth toes.
The neuroma, which can be imaged using ultrasound and
magnetic resonance imaging, likely results from entrapment of
the nerve.10 Footwear, particularly wearing high heels, has been
implicated as one of the causes. Typically, treatments include use
of orthotics, oral analgesics, steroid injection, injection of
sclerosing agents, and surgical neurectomy. Other nonspecific
destructive techniques include thermal lesioning from application
of cold or heat.12 Neurectomy surgery or other percutaneous
Sponsorships or competing interests that may be relevant to content are disclosed
at the end of this article.
a
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
School of Medicine, Baltimore, MD, USA, b Chesapeake Podiatry Group, Owings
Mills, MD, USA, c Centrexion, Baltimore, MD, USA, d Clene Nanomedicine,
Brighton, MI, USA, e Department of Neurosurgery, Johns Hopkins University School
of Medicine, Baltimore, MD, USA
*Corresponding author. Address: Department of Psychiatry and Behavioral
Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Dr,
Suite 100, Baltimore, MD 21224, USA. Tel.: (410) 550-7989; fax: (410) 550-0117.
E-mail address: [email protected] (C. M. Campbell).
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2. Materials and methods
2.1. Design
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destructive interventions do not provide relief of symptoms in
many patients and lead to enduring numbness in the distribution
of the treated nerve.11 According to a Cochrane review,16 there is
insufficient evidence to assess the comparative effectiveness of
surgical and nonsurgical interventions for Morton’s neuroma.
Capsaicin, the pungent ingredient of hot peppers, is an agonist
for the TRPV1 receptor, a member of the transient receptor
potential (TRP) family of ion channels. TRPV1 serves as a sensory
transduction channel for noxious stimulation of skin and other
musculoskeletal tissue, and has thus become a major target for the
development of analgesics. In addition to activating nociceptors
acutely, capsaicin induces long-duration selective analgesia when
applied topically to the skin associated with a loss of epidermal C
fibers.2 The nociceptors grow back over a period of weeks to
months.15 Other studies have suggested that injection of capsaicin
may be helpful in treating postoperative pain and other focal pain
disorders.13 Capsaicin has the potential to be advantageous over
other techniques aimed at destroying the entire nerve, by
selectively affecting only nociceptor function in the area of the
injection. Specifically, capsaicin may relieve pain without affecting
touch sensibility and without inducing scarring.15 In this study, we
examined whether capsaicin was safe and effective in treating the
pain associated with Morton’s neuroma.
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This was a randomized, double-blind, placebo-controlled, singledose, parallel-group study, conducted at 2 sites in the United
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States. The study consisted of 3 scheduled clinic visits: visit 1
(screening), which could occur up to 14 days before the injection
of the study drug; visit 2 (on day 1), which included the injection
procedure and a 4-hour postinjection follow-up in the clinic; and
visit 3, a completion visit at day 28 6 4 (week 4). In addition to the
clinic visits, participants reported safety and efficacy information
through diary cards at postinjection weeks 1, 2, and 3 (see Fig. 1
for a timeline). The protocol and informed consent documents
were approved by the appropriate Institutional Review Boards
and the trial was registered (ClinicalTrials.gov identifier:
NCT00130962). Written informed consent was obtained from
each patient before initiation of study procedures.
2.2. Screening (visit 1)
Participants were medically confirmed to have a painful unilateral
intermetatarsal neuroma as documented by ultrasound or
magnetic resonance imaging. X-ray was performed to help rule
out alternative pathology. Eleven participants had a prior surgical
resection (neurectomy). For entry into the study, subjects were
required to have a score of $4 using the 11-point numeric pain
rating scale (numerical pain rating scale (NPRS): “My average foot
pain severity since my last assessment has been”; 0 5 no pain to
10 5 worst possible pain) during the week before randomization,
and failure of conservative treatment, such as wide shoes,
orthotics, arch supports, or oral analgesics. Subjects were
excluded if they had clinical evidence of other causes of foot
pain or documented allergic reactions to lidocaine or capsaicin.
An abbreviated list of inclusion and exclusion criteria is provided in
Table 1. Review of inclusion and exclusion criteria, complete
medical history, foot pain NPRS, brief physical examination, vital
signs, clinical laboratory specimen examination, ECG, and urine
pregnancy test were conducted at screening. Additionally, the
nonnarcotic analgesic preferred by each participant for managing
his or her neuroma pain was queried for notation in diary cards.
Participants were required to use only this chosen medication as
needed for the duration of the study. Participants completed the
Brief Pain Inventory (BPI)7 interference items (which assess
general activity, mood, walking ability, normal work, relationships,
sleep, and life enjoyment on a 0 [5does not interfere] to 10
[5completely interferes] scale) and were trained in the use of diary
cards for recording pain, interference, and analgesic consumption. The quantity of analgesic medications was recorded weekly
in the diary cards, with notation as to whether it was taken for foot
pain or other pain.
past week. Subjects received an injection of anesthetic (2%
lidocaine with epinephrine; 2 mL) into the third intermetatarsal
space at the base of the proximal phalanges, just distal to the
head of the metatarsals in the region containing the painful
neuroma. After 5 minutes, the study drug (0.5 mL) was injected
into the same site containing either 0.1 mg capsaicin (0.2 mg/mL)
or placebo (polyethylene glycol [PEG] 300 in water for injection in
a 1:1 ratio) in a randomized, double-blinded fashion. The clinician
judged the location of the neuroma by palpating the area of
tenderness in conjunction with using anatomical landmarks. Pain
was rated immediately after injection and at 15, 30, and 45
minutes and 1, 2, 3, and 4 hours after study drug administration. If
pain after study drug administration needed to be treated, the
available options included application of an ice pack until the
symptoms had resolved (up to a maximum of 20 minutes),
administration of up to 2 tablets of Lortab 5/500 (hydrocodone
bitartrate 5 mg and acetaminophen 500 mg) with the potential for
remedication after 4 hours, or an intramuscular injection of
ketorolac (ketorolac tromethamine; Toradol). Vital signs were
reassessed at discharge, and participants were given additional
diary cards. Safety was assessed by tracking the frequency and
severity of adverse events (AEs), comparing pretreatment and
posttreatment urinalysis, blood chemistry, and hematology, as
well as assessing local dermal changes and changes in the heart
rate and blood pressure at the follow-up visit.
2.4. Drug
An unblinded pharmacist or registered nurse prepared all
study drug injection solutions. This person had no further
interaction with the clinician, patient, or other members of the
study team that would affect the double-blind conditions. A
blinding label was attached by the pharmacist or registered
nurse, and the blinded vial was provided to the investigator.
The placebo formulation was identical in appearance, consistency, packaging, and labeling. The placebo and active drug
were manufactured by Formatech, Inc (Andover, MA) and
supplied by the study sponsor.
2.5. Diary cards
Participants rated their average foot pain severity over the
preceding week, interference items from the BPI, and quantity
of analgesics taken for 3 weeks on the diary cards. Study
coordinators called subjects weekly in the event of late or
nonreturned cards.
2.3. Injection day (visit 2)
Inclusion and exclusion criteria, vital signs, and diary cards were
assessed on arrival, and samples for clinical laboratory testing
were obtained. Participants then completed the Average Foot
Pain Severity NPRS and BPI interference items referencing the
2.6. Follow-up (visit 3)
Vital signs, adverse events, physical examination of the feet, and
review of diary cards were assessed at the final study visit,
approximately 4 weeks after injection at visit 2. Participants also
Figure 1. Timeline.
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Table 1
Key inclusion/exclusion criteria.
Inclusion criteria
.18 years of age
Established diagnosis of either a primary or postsurgical recurrence of
a neuroma
Average daily pain score $4 on an 11-point 0-10 numerical pain rating scale
(NPRS) in the area during the week before randomization
Have failed conservative treatment, such as wide shoes, orthotics, arch
supports, or oral and/or injected analgesics
Willingness to limit use of pain relievers to their one chosen analgesic throughout
the study
Exclusion criteria
Other painful foot pathology
Any other chronic medical condition (such as diabetes mellitus or extensive
vascular disease)
Active cutaneous or other disease at the anticipated site of study drug injection
History of clearly documented allergic reaction to lidocaine or capsaicin
Treatment of neuroma with a narcotic analgesic
Requirement for regular oral steroid medication, except for stable use (6 mo or
longer on the same scheduled dose) for mild or moderate asthma
Drug or alcohol abuse within the past 2 years
Cognitive or language difficulties that would impair understanding/completion of
the assessment instruments
Received other experimental drugs within 1 month of randomization
Pregnant or lactating females, planning to become pregnant, or using unreliable
means of birth control
completed a foot pain severity NPRS and the interference items of
the BPI. In addition, the use of analgesics was recorded. ECG
was repeated, and samples for clinical laboratory testing were
obtained.
2.7. Safety
All adverse reactions were recorded through diary cards and
queried at clinic visits. Additional safety evaluation included
examination of vital signs, sensory examination of the foot, touch
sensibility (briefly evaluated by application of a wisp of cotton and
judged to be normal, diminished, or absent), laboratory safety
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parameters, ECG, pain on injection, and dermal responses
assessed at each clinic visit.
2.8. Pharmacokinetics
Blood samples were drawn before study drug injection and at 5,
10, 15, 20, 30, and 45 minutes, and at 1, 1.5, 2, 2.5, 3, and 4
hours after injection for determination of plasma concentrations
of capsaicin. Approximately, 10-mL samples of blood were
collected at each time point.
2.9. Statistical analyses
Chi-square analyses and T-tests were conducted on demographic and baseline data to determine any differences
between groups. The participant’s baseline clinical pain report
(an average of the NPRS provided at screening and preinjection) was subtracted from the NPRS provided every week (in
diary cards for the first 3 weeks and in the clinic in the fourth/
final week) to create change from baseline scores. The BPI
interference scores (7 items) were averaged into 1 score per
week, and change scores were created using the BPI ratings
obtained on the preinjection day. Each BPI interference
question was also examined using change from baseline at
weeks 1, 2, 3, and 4 and compared between groups. Analysis
of covariance was conducted on NPRS change scores at
weeks 1, 2, 3, and 4 (primary endpoint) using baseline (average
of screening and preinjection) pain as a covariate, according to
the original statistical analysis plan for the study. A sum of the
weekly pain ratings was also calculated, and an analysis of
covariance was performed to examine treatment group differences, also using baseline as a covariate. Analysis of
covariances was conducted for BPI interference change
scores each week using preinjection interference as a covariate. Last observation carried forward was used for one
individual who had 1 missing data point (at week 3). A series of t
tests were also conducted to examine participants’ laboratory
tests/pharmacokinetics, plasma concentrations, and use of
preferred drug during the study. Pearson correlation
Figure 2. CONSORT (Consolidated Standards of Reporting Trials) diagram.
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coefficients were calculated to examine whether procedure
pain was related to efficacy. Additionally, a post hoc
cumulative proportion of responders analysis9 was conducted
to evaluate drug effects.
A further post hoc analysis was performed using mixedmodel repeated measures, a likelihood-based analysis in
which subject-specific effects and serial correlation are
modeled through the within-subject error correlation structure. This latter analysis is more appropriate in light of the
longitudinal nature of the data. Specifically, the models
included the effects of treatment, visit, and treatment-byvisit interaction, as well as the baseline pain score as
a covariate; identical analyses were repeated using the BPI
interference data. An unstructured (co)variance structure was
used to model within-patient error. This analysis was
conducted using SAS, a software program capable of nonlinear mixed-effects modeling. Of note, no imputation method
was used for the participant with the missing data point in
these analyses. The primary efficacy analysis and all safety
analyses included all subjects in the intent-to-treat population
(no dropouts).
3. Results
3.1. Participants
Of 67 screened subjects, 58 were randomized (see CONSORT
diagram, Fig. 2). Of the 58 randomized subjects, 28 received
placebo and 30 received capsaicin. Patient demographics,
clinical characteristics at baseline, and other variables of interest
are presented in Table 2.
The 2 randomized groups were well balanced with regard to
demographic characteristics (Table 2). The mean pain level at
baseline was 6.03 (SD 5 1.6; n 5 58). Use of baseline pain
medications was 50.0% in the capsaicin group and 60.7% in the
placebo group.
3.2. Efficacy
Pain and pain interference decreased with time as shown in
Figures 3 and 4. At week 4, the mean reduction in pain from
baseline was larger in the capsaicin group (mean D 5 23.5,
Table 2
Demographics and clinical characteristics.
Variable
Age, mean (SD), years
Sex, n (%)
Female
Male
Race/ethnicity, n (%)
Asian American
Black or African American
Hispanic
Non-Hispanic white
Body mass index (SD)
Pain medications used at baseline (%)
Pain duration, mean (SD)
Neuroma type, n (%)
Primary
Postsurgical
Placebo
(N 5 28)
0.1 mg capsaicin P
(N 5 30)
51.8 (11.8) 53.9 (12.0)
25 (89)
3 (11)
23 (77)
7 (23)
1 (4)
0
0
27 (96)
29.4 (5.2)
17 (60.7)
4.7 (4.6)
0
2 (7)
1 (3)
27 (90)
28.7 (5.6)
15 (50.0)
5.8 (6.6)
22 (79)
6 (21)
25 (83)
5 (17)
Figure 3. Change in average foot pain severity by group ([mean 1 SEM]
y-axis 5 DNPRS; x-axis 5 week). Weekly means rated on the 0- to 10-point
numerical pain rating scale (NPRS) for the capsaicin- and placebo-treated
subjects.
SD 5 2.3; vs mean D 5 22.1, SD 5 2.1; P 5 0.019; Table 3).
A significant reduction of pain was also observed at week 1
(P 5 0.021). The difference did not reach significance at week
2 (P 5 0.099) or 3 (P 5 0.106). A significant drug effect was
also observed in the summed weekly NPRS ratings (P 5
0.023; mean 5 12.9, SD 5 8.6 vs mean 5 17.5, SD 5 8.4).
Figure 3 shows the change in pain for each group separately.
The decline in the BPI interference ratings (7 measures, each
scored from 0 to 10 and averaged) was also greater in the
capsaicin group, though the difference did not reach significance
(capsaicin: mean D 5 221.0, SD 5 16.6; placebo: mean D 5
212.5, SD 5 13.9; P 5 0.090; Fig. 4). However, there was
a significant decrease in certain BPI interference items in the
capsaicin group, as shown in Figure 5. Specifically, measures of
mood (capsaicin group: mean D 5 23.1, SD 5 2.5; vs placebo:
mean D 5 21.3, SD 5 2.6; P 5 0.011) and walking interference
(mean D 5 23.9, SD 5 2.9; vs mean D 5 22.4, SD 5 2.1; P 5
0.029; Fig. 5) improved from baseline to week 4 in the capsaicin
group (P , 0.05). Improvement in measures of sleep and life
enjoyment trended toward significance in the capsaicin group
(P , 0.1).
A cumulative proportion of responders analysis comparing
percent decrease in pain at week 4 to baseline with capsaicin and
placebo is presented in Figure 6. The percentage of subjects
who had at least a 50% (70%, capsaicin vs 43% placebo; P 5
0.037) or 70% (43% capsaicin vs 18% placebo; P 5 0.036)
decrease in pain at 4 weeks was significantly greater in the
capsaicin group.
0.503
0.178
0.268
0.669
0.410
0.479
0.449
P value represents analyses of differences between neuroma groups within each treatment condition as
noted. Medications include nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, and salicylic
acid derivatives.
Figure 4. Change in averaged BPI interference by group and week ([mean 6
SEM] y-axis 5 DBPI interference; x-axis 5 week). Weekly means rated on the
0- to 10-interference scale (0 5 does not interfere, 10 5 completely interferes).
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Table 3
Pain and Brief Pain Inventory (BPI) interference outcomes at baseline and week 4 by the treatment group.
Variable
Placebo (N 5 28)
Full sample
Baseline
Pain severity (SD, 0-10 NPRS)
BPI-Functional Interference Scale, sum (SD)
5.9 (1.5)
29.0 (16.7)
0.1 mg capsaicin (N 5 30)
D week 4 from baseline
22.1 (2.1)
213.8 (13.9)
Baseline
5.9 (1.1)
33.9 (15.1)
P
D week 4 from baseline
23.5 (2.3)
219.7 (16.6)
0.019*
0.090†
P values represent analyses of differences from baseline to week 4 in the capsaicin group compared with the placebo group, controlling for baseline pain/BPI. No differences were observed at baseline between groups. Brief
Pain Inventory (BPI)-functional interference ranges from 0 to 10, higher values represent greater pain/interference.
† P , 0.01.
* P , 0.05.
3.3. Mixed-model repeated measures analyses
Similar to the original analysis, a significant main effect emerged
for drug (P 5 0.023), with those in the capsaicin group having
a greater reduction in pain compared with the placebo group. The
NPRS treatment-by-time interaction analysis indicated that
effects were similar across weeks 1 to 4 (P . 0.05).
3.4. Medications
At each time point, a lower percentage of subjects used
analgesics for foot pain in the capsaicin group than in the
placebo group. However, this was only significant at week
3 (capsaicin: n 5 6 of 30, 20%; placebo: n 5 14 of 28, 50%;
P 5 0.016).
3.5. Safety and adverse events
The injection site evaluation indicated that erythema, edema,
and hemorrhage occurred with similar frequencies in the
capsaicin and placebo groups (rates of 5/30 and 6/28; 15/30
and 21/28; and 10/30 and 7/28; respectively) and were
generally mild or minimal in magnitude. Excluding the pain
reported after study drug administration, the overall adverse
event profile of all causalities and those considered to be
treatment related were similar in both groups (capsaicin: n 5
24; 80%) (placebo: n 5 22; 79%) (Table 4). Capsaicin did not
worsen touch sensibility. At baseline, touch sensibility was
judged to be diminished or absent in 17 of 30 capsaicin
subjects and 9 of 28 placebo subjects. On day 28, repeat
testing revealed that only 7 of 28 of the capsaicin subjects
Figure 5. Change in each Brief Pain Inventory (BPI), functional interference
subscale item by treatment group at week 4 ([mean 6 SEM] y-axis 5 DBPI
interference; x-axis 5 BPI subscale). Each scale is rated on the 0- to 10interference scale (0 5 does not interfere, 10 5 completely interferes); lower
values reflect enhanced improvement from baseline to week 4.
reported reduced sensation, whereas 10 of 27 placebo
subjects reported reduced sensation. Of the treatmentrelated AEs, a larger percentage of the subjects in the placebo
group reported neuropathic pain at any time than subjects in
the capsaicin group (46.3% vs 26.6%, respectively). The
incidence of other treatment-related side effects after drug
injection was similar between both groups. A larger percentage
of capsaicin-treated subjects reported headache (10% vs 0%)
than in the placebo-treated subjects. There were no discontinuations due to an AE. No serious AEs occurred in subjects
receiving capsaicin, whereas 1 subject in the placebo group
experienced a serious AE (subject presented with a precordial
T-wave inversion at 1 week at the planned visit 3 ECG). This
abnormality was resolved without treatment within 3 months.
3.6. Tolerability of procedure pain
Pain after injection was more common in subjects who received
capsaicin than in those who received placebo (100% vs 64.3%,
respectively). The magnitude of pain varied with time in the
capsaicin-treated subjects as shown in Figure 7 and was most
severe immediately after injection (mean NRS score of 8.3 vs 2.3,
for the capsaicin- and placebo-treated groups, respectively).
Postinjection pain was primarily managed with application of
icepacks; in addition, 5 subjects (16.7%) in the capsaicin group
received oral opioids (hydrocodone/acetaminophen 5/500 mg)
for postinjection pain, compared with 1 subject (3.6%) in the
placebo group. Other treatments received by the capsaicin group
included 1 subject who received intramuscular ketorolac and 2
subjects who received ibuprofen 400 mg. By 2 hours after the
injection, pain ratings had diminished to a mean of 4.0 (SD 5 2.1)
in the capsaicin group and 1.5 (SD 5 2.2) in the placebo group.
Change in pain at week 4 was not correlated with the magnitude
of procedure pain (either mean or maximum pain) over 4 hours
(P . 0.05), Figure 8.
Figure 6. Cumulative proportion of responders analysis displaying proportion
of patients who had a given percentage decrease in pain (or more) compared
with baseline at week 4. Of note, 70% of subjects treated with capsaicin had
a 50% decrease in pain compared with 43% of placebo subjects (P 5 0.037).
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Table 4
Adverse events associated with treatment by group.
System/organ class
No. of patients with $1 related adverse
event, n (%)
Pain in the foot
Neuropathic pain and/or sensory symptoms*
Nausea
Headache
Peripheral swelling
Limb discomfort NOS
Contusion
Injection site swelling
Placebo
(N 5 28)
Capsaicin
(N 5 30)
15 (53.6)
15 (50)
3 (10.7)
13 (46.3)
0
1 (3.6)
2 (7.1)
0
2 (7.1)
2 (7.1)
5 (16.7)
8 (26.6)
4 (13.3)
3 (10.0)
3 (10.0)
2 (6.7)
1 (3.3)
0
* Includes burning sensation in the foot, hypesthesia, and paraesthesia.
NOS, not otherwise specified.
3.7. Pharmacokinetics
Capsaicin plasma concentrations were obtained in all participants in the placebo group and for 29 of 30 subjects from the
capsaicin-treated group. No capsaicin was detected in the
placebo group at any of the time points. In the capsaicin group,
both the mean and median time to maximum concentration (Tmax)
were approximately 1 hour, with a mean and median maximum
concentration of 278 pg/mL and 146 pg/mL, respectively. This
discrepancy can be attributed to 3 subjects who had relatively
high plasma concentrations.
4. Discussion
Patients treated with capsaicin as an injection to treat Morton’s
neuroma experienced a significant reduction in pain compared
with the placebo at week 4. The differentiation from placebo was
similar at weeks 1 to 3 as well. This reduction was associated with
the use of fewer pain medications, less functional interference in
mood and walking, and trends suggesting less functional
interference in sleep and life enjoyment, subscales on the BPIshort form. Postinjection adverse events were similar in the
capsaicin- and placebo-treated patients.
4.1. Mechanism for the effects of capsaicin
The term neuroma typically refers to the entangled regenerative
nerve sprouts that occur in response to the division of a nerve in
the situation where reconstitution of continuity with the distal end
of the nerve fails to occur. In the case of Morton’s neuroma, the
“neuroma” is really a neuroma-in-continuity in that the axons likely
remain intact at the point of compression. Nerve swelling
commonly occurs as a sequel of compression and blockade
of axonal transport and is seen in other nerve compression
conditions such as carpal tunnel syndrome and ulnar nerve
entrapment4 (Fig. 9). The metatarsal bones and other soft
tissues near the neuroma are presumed to induce the
compression.5
Capsaicin, a selective TRPV1 agonist, is effective when
given topically to treat neuropathic pain associated with
postherpetic neuralgia, and diabetic neuropathy.8 Benefit
likely results from a reversible loss of nociceptive afferents
from the superficial layers of the skin related to binding to the
TRPV1 receptor. A similar mechanism likely relates to the
effects of capsaicin on the Morton’s neuroma. The axons that
are subject to compression may initiate action potentials
ectopically and thus signal pain and cause paresthesias.
TRPV1 is robustly expressed at the axonal level in C fibers.3
Moreover, calcitonin gene-related peptide, a marker for
nociceptors, is released locally in response to capsaicin
application to nerves in rodents. This release was found to
be Ca11 dependent and was blocked by administration of
TRPV1 antagonists, and furthermore, was not observed in
TRPV1 knockout mice. These results support the hypothesis
that capsaicin effects are mediated by the TRPV1 receptor.
Capsaicin may initially induce excitation at the axonal level of
nociceptive afferents but subsequently induce a selective
axotomy. Of note, nervi nervorum nerve fibers also express
TRPV1 receptors, raising the possibility that capsaicin exerts
its effects by selectively affecting these fibers, as opposed to
the nerve fibers of passage (Fig. 9).3,14
The mean drop in pain of 3.5 was high relative to the level of
baseline pain. One could nevertheless ask whether an even more
substantial effect could be achieved. The lack of a stronger effect
could be related to one or all of the following possibilities: (1)
a ceiling effect (given that the mean drop in pain in the active
group was substantial relative to the pain at baseline); (2)
a pharmacokinetic issue given limitations of drug delivery; (3)
pain mechanisms in Morton’s neuroma related to afferents that
do not express TRPV1; or (4) misdiagnosis (pain mechanisms in
part or completely unrelated to Morton’s neuroma and not
amendable to capsaicin treatment). Further dose-ranging studies
may help in distinguishing these possibilities.
4.2. Dosing and duration of effect
Figure 7. Numerical pain rating scale (NPRS, 0-10) ratings of capsaicin
injection pain over 4 hours in the capsaicin and placebo groups for all subjects
([mean 6 SEM] y-axis 5 NPRS; x-axis 5 time in minutes).
Given that this was an exploratory study, there is more to learn
regarding dosing, control of procedure pain, and durability of
effect. High-dose capsaicin applied topically to the skin to treat
neuropathic pain seems to be effective for at least 12 weeks.8
Simone et al.15 explored the issue of dose and duration of effect in
the skin of normal human subjects given intradermal capsaicin in
the upper arm, as determined by psychophysical testing and skin
biopsy. Capsaicin was given in doses that ranged up to
20 mg/20 mL (0.1%). At the 20 mg dose, there was a complete
loss of intraepidermal nerve fibers, which corresponded to a loss
of heat pain sensation. These effects were evident at 72 hours
after injection and persisted for several weeks. Touch sensibility
was unaffected. In the present study, the dose was greater
(0.1 mg), but the percent concentration was less (0.02%), given
the much higher volume of injectate. How dosing to a nerve
(actually a neuroma-in-continuity) corresponds to dosing in the
skin is as yet unknown.
Copyright Ó 2016 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
June 2016
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Figure 8. Scatterplots of the summed procedure pain over 4 hours (x-axis; 8 ratings, 0-10 each: maximum possible 5 80) and change in pain at week 4 (DNPRS, yaxis) in the placebo (panel A) and capsaicin (panel B) groups for all subjects. The change in pain did not vary with the degree of procedure pain in either the placeboor capsaicin-treated subjects.
Capsaicin seems to be metabolized quickly by cytochrome
enzymes in the human liver.2 In this study, the mean capsaicin
concentration was 278 pg/mL (0.28 ng/mL), lower than the levels
that may be reached with dietary capsaicin (2.5 ng/mL)6 and
levels reached after application of 8% topical (1.86 ng/mL)2
capsaicin. The maximum concentration in this study was noted at
approximately 1 hour, which is similar to that observed with
ingested and topically applied capsaicin, where the reported Tmax
was 47 and 60 to 90 minutes, respectively.2,6 Some diets contain
capsaicin at levels more than 50-fold the amount of capsaicin
used in this study.1,6
4.3. Pain with injection
All subjects who received capsaicin experienced pain with
injection. Similarly, high pain scores have been reported in
studies with topical high-dose capsaicin as treatment for
neuropathic pain. By 4 hours after injection, the mean pain level
was mostly resolved (mean level, 2.0). In the placebo group, the
mean maximum pain score was 3.3 but ranged from 0 to 10. A
high procedure-related pain score would suggest that the subject
was in the capsaicin group and could be argued to interfere with
blinding. It could be that increased procedure pain in the active
group may have biased the outcome. To explore this possibility,
we determined separately in the placebo and active groups how
the change in pain varied with both peak pain and pain in
aggregate over 4 hours. Figure 8 shows that in this analysis,
procedure pain had no association with the change in pain at
4 weeks.
5. Conclusions
This study demonstrates that injection of capsaicin locally is
a promising new treatment of Morton’s neuroma. Further aspects
of this therapy warrant consideration in future studies.
Conflict of interest statement
M. Kelly and W. K. Schmidt consult for Centrexion Therapeutics.
R. Allen is a former employee of Centrexion Therapuetics. K. L.
Brady and J. N. Campbell are employed by Centrexion
Therapeutics. The other authors have no conflicts of interest to
declare. Drs. Claudia and James Campbell’s participation as
authors in this publication were as contributors for Centrexion. All
opinions expressed and implied in this publication are solely those
of Drs. Claudia and James Campbell and do not represent or
reflect the views of the Johns Hopkins University or the Johns
Hopkins Health System.
Acknowledgements
CNTX4975, injectable capsaicin, is an investigational drug under
development by Centrexion Therapeutics. The trial was originally
designed, sponsored, and administered by AlgoRx Pharmaceuticals, Inc. In December 2005, AlgoRx merged with Anesiva,
Inc, the relevant assets of which were then acquired by the current
sponsor, Centrexion Therapeutics. The authors thank Jennifer
Nezzer and Shari Medendorp, of Premier Research, for their
mixed-model analyses and statistical support.
Article history:
Received 19 November 2015
Received in revised form 12 January 2016
Accepted 29 February 2016
Available online 8 March 2016
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Figure 9. Model of Morton’s neuroma indicating the point of compression, the
nerve swelling (neuroma) just proximal to the compression, the axons in
passage, and the innervation of the nerve sheath (nervi nervorum). Given the
clinical finding of point tenderness over the region of the neuroma, it is likely
that the signals for pain arise from activation of the nervi nervorum. Capsaicin
may exert a therapeutic effect by way of effects on these nerve fibers.
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