SPECIAL TOPIC SERIES

Selected CAM Therapies for Arthritis-Related Pain:

The Evidence From Systematic Reviews
Karen L. Soeken, PhD
Objectives: The purpose is to examine what is known about the
efficacy of selected complementary and alternative medicine (CAM)
therapies for pain from arthritis and related conditions based on sys-
tematic reviews and meta-analyses.
Methods: Results specifically related to pain were retrieved from
reviewarticles of acupuncture, homeopathy, herbal remedies, and se-
lected nutritional supplements.
Results: Evidence exists to support the efficacy of reducing
pain from osteoarthritis (OA) for acupuncture; devils claw,
avocado/soybean unsaponifiables, Phytodolor and capsaicin; and
chondroitin, glucosamine, and SAMe. Strong support exists for
gamma linolenic acid (GLA) for pain of rheumatoid arthritis (RA).
Conclusions: Despite support for some of the most popular CAM
therapies for pain from arthritis-related conditions, additional high
quality research is needed for other therapies, especially for herbals
and homeopathy.
Key Words: complimentary and alternative medicine, acupuncture,
homeopathy, herbal therapy
(Clin J Pain 2004;20:1318)
A
n estimated 30%to 70%of patients in developed countries
use Complementary and Alternative Medicine (CAM),
that is, practices that are not presently considered an integral
part of conventional or mainstream medicine. It was estimated
that 60 million adults in the US used CAM in 1990 with that
number growing to 83 million by 1997, an increase of almost
40%.
1
Usage seems to be primarily for back pain, allergies,
fatigue, arthritis, and headaches. In fact, those who use CAM
regularly are more likely to be those experiencing severe pain.
For example, in a 1997 survey of patients with rheumatic dis-
eases, more than 60% indicated they had used some type of
alternative care.
2
CAM includes a wide variety of therapies
that can be categorized into 5 major domains: alternative medi-
cal systems such as acupuncture and homeopathic medicine,
mind-body interventions, biologically based therapies that in-
clude herbal remedies, manipulative and body-based methods,
and energy therapies.
As a general rule, CAM therapies have been under-
researched as compared with conventional therapies. How-
ever, a growing body of empirical evidence has led to system-
atic reviews and meta-analyses for some of the therapies and
some of the conditions. At present there are over 200 review
articles in CAM, including systematic reviews and meta-
analyses, with approximately 80 for arthritis and related
di seases ( avai l abl e at ht t p: / / www. campai n. umm.
edu/ris/risweb.isa). The purpose of this paper is to summarize
what is known about the efficacy of selected CAM therapies
for pain from arthritis and related diseases based on these re-
views. The focus will be on acupuncture, homeopathy, herbal
remedies, and selected nutritional supplements.
ACUPUNCTURE
Acupuncture is growing in popularity in the US and is
used by an estimated 1 million Americans annually, primarily
for pain relief.
3
There have been approximately 500 random-
ized clinical trials (RCTs) of acupuncture and more than 25
systematic reviews and meta-analyses for various conditions.
4
Acupuncture is thought to correct imbalances in the flow of
energy through meridians that connect the body. By selecting
appropriate points from among the 365 points distributed
along the meridians, the practitioner can restore balance and
promote health.
Acupuncture and Osteoarthritis
Two reviews for acupuncture and osteoarthritis (OA)
have synthesized the results of individual trials. (See Table 1
for a summary of reviews.) One included 13 studies published
between 1975 and 1996.
5
Of this number, 10 were RCTs in-
volving 331 patients with OA in various locations. Compari-
son groups included piroxicam, transcutaneous nerve stimula-
Received for publication October 16, 2002; accepted October 16, 2002.
From the University of Maryland, School of Nursing and School of Medicine,
Complementary Medicine Program, Baltimore, Maryland.
This work was supported by grant #5-P50-AT00084-02 from the National
Center for Complementary and Alternative Medicine, National Institutes
of Health.
Reprints: Karen L. Soeken, PhD, University of Maryland School of Medicine,
Complementary Medicine Program, Kernan Hospital Mansion, 2200 Ker-
nan Drive, Baltimore, MD (e-mail: ksoeken@compmed.umm.edu).
Copyright 2003 by Lippincott Williams & Wilkins
Clin J Pain Volume 20, Number 1, January/February 2004 13
tion (TENS), sham TENS, physiotherapy, and sham acupunc-
ture. Considering just the RCTs included in the review, 5 of the
10 trials were positive for acupuncture, that is, supported acu-
puncture. Of the 5 RCTs that compared acupuncture to sham
acupuncture, only 1 found acupuncture superior to needling of
non-acupuncture points in reducing pain. In the other 4 trials,
acupuncture did not produce increased reduction in pain as
compared with sham. Two of these trials used double-blinding
and both concluded that acupuncture is not superior to sham-
needling.
Unfortunately trial quality was not systematically re-
ported in the review and no effect sizes (ES) were reported
although there was apparently low statistical power in 3 of the
studies. Based on this review, there is no consistent evidence to
suggest that acupuncture is superior to sham needling in alle-
viating pain of axial and peripheral joint OA. Rather, acupunc-
ture and sham acupuncture appear to have similar positive ef-
fects in reducing pain. It may be that sham-needling produces
specific effects through the release of endorphins, suggesting
the need to identify an appropriate sham procedure for acu-
puncture. An alternative explanation is that both acupuncture
and sham-needling demonstrate powerful placebo effects sug-
gesting that the placebo effect in CAM or the role of patient
beliefs and expectations needs further study.
A second review examined acupuncture for OA of the
knee.
6
This review included 7 trials, all described as random-
ized, with almost 400 patients. The authors used an extensive
search strategy to identify studies and they formally rated trials
for study quality using the Jadad scale
7
that assesses random-
ization, blinding, and the reporting of withdrawals and drop-
TABLE 1. Summary of Reviews Related to Complementary and Alternative Therapies for Reducing Pain
CAM Therapy Condition Review Year
Type of
Review* Conclusions
Acupuncture Osteoarthritis Ernst
5
1997 SR Acupuncture and sham-needling produce
similar results.
Osteoarthritis of the
knee
Ezzo
6
2001 SR Acupuncture superior to wait list but not
different as compared to physical therapy;
moderate support as compared to
sham-needling.
Rheumatoid
arthritis
Batt-Sanders
8
1985 NR None can be drawn.
Fibromyalgia Berman
11
1999 NR Some support for acupuncture as compared to
sham acupuncture.
Homeopathy Arthritis and
related diseases
Jonas
13
2000 MA Homeopathic remedies were twice as
effective as placebo.
Herbal therapy Osteoarthritis Little
15
2002 MA/SR Avocado/soybean unsaponifiables appear to
provide long-term relief for those with OA
of the hip.
Osteoarthritis Long
16
2001 SR Promising support for devils claw and
avocado/soybean unsaponifiables; moderate
support for Phytodor and topical capsaicin.
Rheumatoid
arthritis
Little
19
2002 NA/SR Borage seed oil, evening primrose oil, and
blackcurrant seed oil significant as
compared to placebo.
Glucosamine Osteoarthritis of the
knee
McAlindon
20
2000 MA Moderate treatment effect for glucosamine as
compared to placebo.
Osteoarthritis Towheed
21
2002 MA Large treatment effect for glucosamine as
compared to placebo and NSAIDs.
Chondroitin sulfate Osteoarthritis of the
hip or knee
Leeb
23
2000 MA Chondroitin in combination with analgesics or
low dose NSAIDs is more effective than
analgesics or NSAIDs alone.
Osteoarthritis of the
knee
McAlindon
20
2000 MA Large effect for chondroitin as compared to
placebo.
SAMe Osteoarthritis Soeken
24
2002 MA SAMe effective as compared to NSAIDs.
*MA, Meta-analysis; SR, systematic review; NR, narrative review.
Results do not apply strictly to pain outcome.
Not all RCTs in an herbal review assess the same herbal.
Soeken Clin J Pain Volume 20, Number 1, January/February 2004
14 2003 Lippincott Williams & Wilkins
outs. Three different types of comparison groups were used: a
wait list or standard treatment (n = 2), physical therapy (n = 2),
and sham acupuncture (n = 3).
Of the 2 trials that used a wait list or treatment as usual,
1 was rated low quality and 1 high quality, but results were
consistent in showing acupuncture as more efficacious in re-
ducing pain. Both trials that used physical therapy as the com-
parison group were rated of low quality and both showed neu-
tral results. That is, there was no difference between physical
therapy and acupuncture in terms of the pain outcome leading
to inconclusive evidence given the quality of the trials. Three
high quality trials compared acupuncture to shamacupuncture,
the needling of non-acupuncture points. One trial had positive
results, 1 had neutral results, and 1 had inconsistent results
across different pain measures. Given the inconsistent results
across the 3 trials, there appears to be moderate evidence at
best for acupuncture for OA of the knee as compared with
sham acupuncture. More evidence is needed in this area.
Several factors may account for the different conclu-
sions about the efficacy of acupuncture reached in these 2 re-
views. First, Ezzo et al
6
limited their studies to OA of the knee
whereas Ernst
5
considered OAin any location. While the latter
strategy resulted in a broader review in terms of patient popu-
lation, site of OA was not considered when synthesizing the
study results. Second, there were 2 studies in the OA of the
knee review that were not included in the earlier review al-
though they had been published in 1981 and 1994, not surpris-
ing given that the search strategies differed in their complete-
ness. Third, the broader review presented no systematic data
concerning quality ratings and consequently study quality was
not considered when drawing conclusions. Finally, neither re-
view presented effect sizes for the individual trials citing het-
erogeneity in the types of control groups and insufficient data
reporting. As a result it is difficult to determine whether and to
what extent the lack of statistical significance in the individual
trials reflects lowstatistical power. There may have been stud-
ies, for example, with moderate or even large effect sizes
but insufficient power to declare the results statistically
significant.
Acupuncture and Rheumatoid Arthritis
No systematic reviewof acupuncture and rheumatoid ar-
thritis (RA) was located. There was 1 literature review pub-
lished in 1985
8
that included 5 double-blinded studies of pa-
tients with RA, only 3 of which were described as controlled
trials. Two included patients with knee pain. One RCT with 20
patients reporting pain in both knees showed acupuncture
more effective than sham in relieving pain for up to 3 months.
Another found no significant difference in pain reduction be-
tween acupuncture and sham based on a sample of 28 patients
with knee pain. The third RCT was a pilot study presented as
an abstract with no data reported. Subsequently there have
been 2 additional non-RCTs.
9,10
Obviously no conclusions can
be drawn from these trials and more high quality research is
needed to determine the efficacy of acupuncture for RA.
Acupuncture and Fibromyalgia Syndrome
Based on an extensive search strategy, 7 studies were
located for a review that examined acupuncture and fibromy-
algia (FMS).
11
Three were RCTs and 4 were cohort studies, 3
prospective and 1 retrospective. Comparison groups in the
RCTs were heterogeneous: sham acupuncture, antidepressant,
and deactivated laser. Based on the 1 RCT that was rated as
high quality using the Jadad scale, acupuncture is more effec-
tive than sham acupuncture in pain relief and pain threshold.
However, almost one-third of the patients in the acupuncture
group dropped out of the study for reasons related to the pro-
cedure itself, with half of the dropouts reporting exacerbation
of symptoms. One of the low quality studies also showed acu-
puncture more effective for pain intensity, localized pain rat-
ing, and pain threshold, while the other low quality RCT did
not present between-group comparisons. Although there is a
limited support for acupuncture for FMS as compared with
sham acupuncture on the basis of 1 high quality RCT, an im-
portant finding is that some patients reported an exacerbation
of their FMS-related pain with acupuncture.
HOMEOPATHY
Homeopathy is based on two main tenets.
12
The first is
the principle of similars, which states that patients with a
particular pattern of signs and symptoms can be cured if they
are given a drug that produces the same pattern of signs and
symptoms when given to a healthy individual. This means that
treatment is individualized. The second tenet is that remedies
retain biologic activity if they are diluted and agitated or
shaken between serial dilutions, even if no original molecules
remain.
Only 1 meta-analysis was located that examined home-
opathy and arthritis and related diseases.
13
Six trials that used
either random assignment or double-blinding were included.
Three trials used patients (n = 266) with RA while subjects in
the other 3 trials had OA, FMS, and myalgia. The interventions
varied and included individualized or classic homeopathic
treatment as well as complex homeopathy in which one or
more remedies are administered for standard clinical condi-
tions. The outcomes varied alsoglobal assessment, treat-
ment preference, or predefined responder criteriaso the re-
sults summarized do not apply strictly to pain. However, using
the Jadad scale,
7
5 of the 6 trials were rated as high quality.
Results were presented as an odds ratio (OR) such that a value
greater than 1 indicates greater effectiveness of homeopathy as
compared with placebo. Based on meta-analysis, homeopathy
was more effective than placebo whether one looks at all 6
trials [OR = 2.19, CI
95
(1.55, 3.11)] or only the 5 high quality
studies [OR = 2.11, CI
95
(1.32, 3.35)]; homeopathic remedies
were twice as effective as placebo. Although the number of
Clin J Pain Volume 20, Number 1, January/February 2004 Selected CAM Therapies for Arthritis-Related Pain
2003 Lippincott Williams & Wilkins 15
studies is small and the results are mixed, it does appear that
homeopathic remedies work better than placebo for rheumatic
syndromes. However, the small number of studies limits any
definitive conclusion concerning the efficacy of any one type
of homeopathic treatment of any one condition. In general,
there are quality concerns for homeopathic clinical trials
across all conditions.
14
Almost all studies failed to report the
proportion of subjects screened, over half did not report attri-
tion rate, and there was little replication of conditions studied.
Further research of homeopathy is warranted.
HERBAL THERAPY
Herbal Therapy and OA
Many herbals are touted for OA. Among the most popu-
lar are Thunder God vine (Radix Tripterygium wilfordii hook
F), devils claw, plant seed oils such as evening primrose and
borage seed, and willow bark (Salix species). Two systematic
reviews were located for herbals and OA. The first is a Co-
chrane review last updated in 2000.
15
Using an extensive lit-
erature search, the authors identified 5 RCTs of 4 different
herbal interventions as compared with placebo. Two of the tri-
als involved avocado/soybean unsaponifiables (ASU); other
herbals were topical capsaicin, Tipi tea (Petiveria alliacea),
and Reumalex, an over-the-counter preparation that contains
willowbark. The 2 RCTs of ASUwere both rated of high qual-
ity on the Jadad scale and included 327 patients. The pooled ES
for these 2 trials indicated ASU produced a significant de-
crease in pain as compared with placebo. Results for the topi-
cal capsaicin and Reumalex trials, both rated of high quality,
were also positive for pain although the results for Tipi tea
showed no difference as compared with placebo. All herbals
were well tolerated. It is difficult to drawconclusions based on
the single studies. However, ASU appears to provide long-
term symptomatic relief, particularly for patients with OA of
the hip. Evidence also suggests that ASU may help patients to
reduce their consumption of NSAIDs.
The second review
16
was based on 12 trials that involved
9 herbals and 2 previous systematic reviews, one of topical
capsaicin
17
and the other of Phytodolor,
18
a fixed herbal for-
mulation containing alcoholic extracts of Populus tremula,
Fraxinus excelsior, and Solidago virgaurea. This systematic
review was broader than the previous because trials of herbals
against active comparators were included. All but 1 of the in-
dividual trials were rated of high quality using the Jadad scale.
Some herbalsginger, aspen, milfoil, and Gitadyl, a formula-
tion containing feverfewshowed no significant results based
on a single trial, while the Ayurvedic formulation Ezmov was
significantly inferior to diclofenac in reducing pain severity. In
the other single trials of an herbal, results were positive for
willowbark, Reumalex (which contains willowbark), stinging
nettle applied topically, and Articulin-F, an Ayurvedic formu-
lation containing Withanias, in significantly reducing pain.
However, no conclusions can be drawn with respect to the ef-
ficacy of any of these herbals in reducing pain based on only a
single trial.
For devils claw and ASU there is promising support for
pain reduction based on 2 high quality trials that demonstrated
significant results, while moderate support exists for Phytodo-
lor and topical capsaicin, defined as 3 or more high quality
trials favoring the herbal. For example, in the 3 trials included
in the meta-analysis of capsaicin, the OR = 4.36 favoring cap-
saicin with the additional trial located demonstrating consis-
tent significant reduction in pain.
In addition to the support for herbals in reducing pain,
the incidence of adverse effects related to the herbals was
low. There were some limitations noted for the trials included
in this review. Specifically, some trials failed to state
inclusion/exclusion criteria, compliance, and withdrawals.
Others did not distinguish between patients with mild and se-
vere forms of OA or they did not distinguish among joint lo-
cation of OA. Still others did not mention the concomitant use
of NSAIDs or analgesics. Although there are hundreds of
herbal remedies that are used for or claimed to be effective for
OA, the research literature reflects only a small percentage of
these remedies and more research in this area is needed.
Herbal Therapy and RA
A review of herbal therapy and RA
19
was based on an
extensive search strategy for herbals versus placebo, excluding
any preparation of synthetic origin or consisting only of plant
derivatives. The review included 11 trials. Pooled results from
trials of gamma linolenic acid (GLA) found in borage seed oil,
evening primrose oil, and blackcurrant seed oil showed signifi-
cant reduction in pain as compared with placebo. GLA sup-
presses release of inflammatory mediators, perhaps by a direct
effect on T cells. Other herbals studied included feverfew,
Tripterygium wilfordii hook F (T2), topical capsaicin, and
Reumalex which contains willow bark. With the exception of
GLA, then, the available evidence for herbal treatment of RA
is lacking and more studies are needed before conclusions
about efficacy can be drawn.
NUTRITIONAL SUPPLEMENTS
Glucosamine for OA
Glucosamine is a slow-acting drug for the treatment of
osteoarthritis. In addition to its effects on cartilage metabo-
lism, anti-inflammatory effects have been found in rat models.
One meta-analysis
20
included 6 double-blinded trials of glu-
cosamine versus placebo that were of at least 4 weeks duration.
Although not an inclusion criterion, all patients had OA of the
knee. Quality of the trials was assessed using an instrument
that assigned a score for each of 14 aspects of clinical trial
conduct with quality scores averaging 35.5% of the possible
points. Using the outcome stated in the primary research to be
Soeken Clin J Pain Volume 20, Number 1, January/February 2004
16 2003 Lippincott Williams & Wilkins
the main outcome measure, a moderate treatment effect was
found (mean standardized difference between groups = 0.44,
CI
95
0.24.64). Across the 3 trials in which pain was the pri-
mary outcome, the overall effect size was 0.51 (CI
95
0.05.96).
Further, study quality was related to effect size: studies with
quality scores above the median tended to report a lower effect
size than those belowthe median (0.70 vs. 0.30). However, this
analysis by trial quality was not restricted to the pain outcome.
Another meta-analysis of glucosamine included RCTs
with placebo or comparators.
21
Sixteen RCTs with over 2000
subjects were included: all were double-blind trials, 13 trials
compared glucosamine to placebo, 12 evaluated the knee ex-
clusively, and 14 were at least 4 weeks in duration. (The 2
reviews have only 5 double-blinded placebo-controlled RCTs
in common despite reporting a similar search strategy covering
approximately the same time period.) Methodological quality
averaged 9 out of 16 on the Gotzsche checklist
22
and all trials
were considered high quality on the Jadad scale. As compared
with placebo, glucosamine demonstrated an ES of 1.40 for
pain reduction across 7 trials with a pooled effect size of 0.86
when compared with an NSAID across 4 trials. Both of these
are considered large treatment effects. In 2 of the trials against
NSAIDs, glucosamine was positive for pain reduction whereas
in the other 2, glucosamine and NSAID produced equivalent
pain reduction. In addition, glucosamine was relatively well
tolerated: only 14 subjects (1.5%) randomized to glucosamine
withdrew because of toxicity and less than 10% of subjects
reported glucosamine-related adverse reactions. Results
suggest strong support for glucosamine in the pain manage-
ment of OA.
Chondroitin Sulfate for OA
Chondroitin sulfate also has anti-inflammatory effects
as well as an effect on cartilage metabolismalthough the mode
of action is not completely understood. One meta-analysis in-
cluded 7 double-blind RCTs of 700 patients with hip and knee
OA.
23
Studies were not assessed for quality as part of the meta-
analysis although the authors noted that some studies were ex-
cluded from the analysis because of design flaws or small
sample sizes. All individual trials were consistent in demon-
strating significant reduction in pain as compared with pla-
cebo. Overall, pain as assessed by a visual analog scale de-
clined to 57%of baseline in the chondroitin group as compared
with 80% of baseline in the placebo group, a large treatment
effect size of 0.90. Treatment duration in the trials ranged from
2 to 12 months and dosage ranged from 800 to 2000 mg/d al-
though dosage was not related to decrease in pain. Side effects
were mild and were primarily gastrointestinal in about 10% of
the patients. Because acetaminophen or low dose NSAIDs
were permitted as additional medication in both the treatment
and control groups, the results support the efficacy of chon-
droitin sulfate in combination with analgesics or low dose
NSAIDs as compared with analgesics or NSAID alone in the
treatment of pain related to OA of the hip or knee.
Nine double-blind RCTs of chondroitin versus placebo
involving 800 patients with OA of the knee were included in
another more specific review.
20
Only trials of at least 4 weeks
duration were included given the slow-acting nature of chon-
droitin. A potential limitation is that in 8 of the trials there was
some level of manufacturer sponsorship, including 4 trials in
which the manufacturer conducted key aspects of the trial (ran-
domization, data collection, or statistical analysis). The mean
quality score for the studies was 34.3% of the maximum score
possible. Considering the pain outcome, the overall effect size
for 8 trials was large (ES = 0.86, CI
95
0.641.09) showing a
significant reduction in pain for patients using chondroitin as
compared with placebo. Given the methodological limitations
of inadequate allocation concealment, absence of intent-to-
treat approaches, publication bias, and the smaller effect sizes
among larger trials, it is possible that the actual efficacy is
somewhat less. Nevertheless, evidence supports the efficacy of
chondroitin preparations for pain from OA.
SAMe (S-adenosylmethionine)
SAMe is a dietary supplement said to promote joint com-
fort. Eleven RCTs comparing SAMe with placebo or NSAIDs
in a sample of patients with a diagnosis of OAwere included in
a meta-analysis.
24
Almost 1500 patients were included in the
trials, all rated to be of high quality using the Jadad scale. The
majority of patients had OA of the knee. Although SAMe
failed to produce a significant reduction in pain when com-
pared with placebo, this was based on only 2 trials. However,
SAMe does appear to be as effective in reducing pain (ES =
.12) as compared with NSAIDs regardless of dosage of SAMe
or duration of trial. In addition, SAMe treated patients were
58%less likely to experience adverse effects than those treated
with NSAIDs.
SUMMARY
What have these reviews indicated about the efficacy of
specific CAM therapies for pain from arthritis and related dis-
eases? First, there are a sufficient number of studies in some
areas despite claims often heard about the lack of evidence for
CAM. Second, research findings for some of the CAM thera-
pies reviewed here have demonstrated consistent beneficial
outcomes for patients with arthritis and related diseases. Spe-
cifically, there is moderate support for acupuncture in reducing
pain as compared with sham acupuncture and limited support
for acupuncture as compared with a wait list for OA of the
knee. However, no claims can be made for the superiority of
acupuncture across locations of OA and across comparison
groups. Further, only limited support exists for the efficacy
of acupuncture for FMS with the caveat that acupuncture
may actually exacerbate the pain for some patients with
Clin J Pain Volume 20, Number 1, January/February 2004 Selected CAM Therapies for Arthritis-Related Pain
2003 Lippincott Williams & Wilkins 17
FMS. At this point, little is known about acupuncture for pa-
tients with RA.
Homeopathy has been demonstrated to be twice as effi-
cacious as placebo for rheumatic conditions, but the outcome
was not specifically pain. Furthermore, the interventions in-
cluded both simple and complex homeopathy as well as indi-
vidualized and standard treatments and may not represent the
systemof homeopathy as practiced. More research is needed in
this area.
Some herbals and nutraceuticals are also beneficial in
reducing pain. Both avocado/soybean unsaponifiables and
devils claw demonstrated promising support for pain of OA
with moderate support for Phytodolor and topical capsaicin.
Among the herbals used for or promoted for RA, there is strong
support for GLA as found, for example, in borage seed oil,
evening primrose oil, and blackcurrant seed oil. However, evi-
dence is lacking for other herbals and more high quality re-
search is needed. Research findings also support the benefits of
chondroitin sulfate, glucosamine, and SAMe in reducing pain,
particularly pain related to OA of the knee. Furthermore, these
treatments appear safe to use.
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18 2003 Lippincott Williams & Wilkins