Update on the
Use of Vitamin B12 in Management of pain
......................................................................................................................................................................
A. Abyad
Correspondence:
A. Abyad, MD, MPH, MBA, AGSF , AFCHSE
CEO, Abyad Medical Center
Chairman, Middle-East Academy for Medicine of
Aging
President, Middle East Association on Age &
Alzheimer's
Coordinator, Middle-East Primary Care Research
Network
Coordinator, Middle-East Network on Aging
Email:
aabyad@cyberia.net.lb
ABSTRACT
Methylcobalamin (MeCbl), the activated
form of vitamin B12, has been used to manage
some nutritional diseases and other diseases
in the clinic, including Alzheimer's disease
and rheumatoid arthritis. As an adjuvant,
it effects neuronal protection by fostering
regeneration of injured nerves and alienating
glutamate-induced neurotoxicity. Recently
several studies revealed that MeCbl may
have conceivable analgesic effects in experimental
and clinical studies. It can reduce, pain
behaviors in diabetic neuropathy, low back
pain and neuralgia. MeCbl ameliorate nerve
conduction, stimulated the regeneration
of injured nerves,
and inhibited ectopic spontaneous discharges
of injured primary sensory neurons.
Low back pain is an everyday
problem worldwide. It can lead to a great
financial burden to society due to absenteeism
or having work limitations. Back pain is
one of the most common symptoms for seeing
primary care physicians and one of the top
5 causes of surgery.
Recent studies have shown
a correlation between vitamin B12 injection
and a decrease in Low back pain. This review
aims to synopsize the analgesic effect and
mechanisms of MeCbl at the present with
particular stress on chronic low back pain.
Intramuscular vitamin B12 injections appear
to be of benefit in the reduction of chronic
low back pain and also improve associated
disability. However, further research is
necessary to study the possible long term
adverse reactions of these intramuscular
injections.
Key words:
Vitamin B12, methylcobalamin, low back pain
|
Vitamin
B12 is essential for the health of our nervous
system and blood cells, and vitamin B12 replacement
is known for its role in the treatment of peripheral
neuropathy and megaloblastic anemia (1).
Vitamin B12 is one of the body's
main building blocks, assisting it to make DNA
and keep nerves and blood tissue vigorous. Vitamin
B12 is present in animal products, including beef,
seafood, milk, and cheese. Therefore, vegetarians
run the risk of having vitamin B12 deficiencies.
Vitamin B12 is essential for prime health. Even
in the absence of deficiency, shots of the vitamin
have been considered recently as an alternative
therapy for chronic conditions, including back
pain.
Traditionally vitamin B12 had
been used to treat anemic elderly patients and
as an adjuvant in sport nutrition. It was considered
as a painkiller since 1950 in some countries.
Lately studies have shown that vitamin B12 played
a major part in the normal functioning of the
brain and nervous system and the formation of
blood. Vitamin B12 is generally implicated in
several metabolisms such as DNA synthesis and
regulation, fatty acid synthesis, and energy production.
Vitamin B12 has some analogs including cyanocobalamin
(CNCbl), methylcobalamin (MeCbl), hydroxocobalamin
(OHCbl), and adenosylcobalamin (AdoCbl). In mammalian
cells, CNCbl and OHCbl are inactive forms and
AdoCbl acts as a coenzyme of methylmalonyl Co-A
mutase in mitochondria. However, vitamin B12 was
not used directly in the human body, and it should
be translated into activating forms such as MeCbl
or AdoCbl. MeCbl differs from vitamin B12 in that
the cyanide is replaced by a methyl group (2).
It is a coenzyme of methionine synthase, which
is needed for the formation of methionine from
homocysteine in the methylation cycle which includes
methylation of DNA or proteins (3-6). Compared
with other analogs, MeCbl is the most effective
one in being uptaken by subcellular organelles
of neurons. Therefore, MeCbl can provide better
treatments for nervous disorders through effective
systemic or local delivery.
As a supporting agent, MeCbl
has been forever used to manage several diseases,
such as B12 deficiency and Alzheimer's disease
syndromes (7, 8). L-methylfolate, MeCbl, and N-acetylcysteine
ameliorate memory, emotional functions, and communication
with other people among Alzheimer's patients (8,9).
MeCbl also has neuronal protection embracing promoting
injured nerve and axonal regeneration (10, 11)
and antagonizing glutamate-induced neurotoxicity
(10, 12). In addition, MeCbl amended nerve conduction
in either patients of diabetic neuropathy (13-15)
or streptozotocin-diabetic rats (16) and experimental
acrylamide neuropathy (17). MeCbl also enhanced
visual function (18), rheumatoid arthritis (19),
Bell's palsy, and sleep-wake rhythm disorder (20,
21). Lately, MeCbl has been revealed to have possible
analgesic effects on neuropathic pain in experimental
and clinical studies.
2.
THE ANALGESIC EFFECT OF MeCbl |
MeCbl is one active form of vitamin
B12 which can directly participate in homocysteine
metabolism. Accumulating evidence is showing the
beneficial effects of MeCbl on clinical and experimental
peripheral neuropathy.
2.1. Diabetic Peripheral Neuropathic Pain
Paraesthesia, burning pains,
and spontaneous pain in legs, were ameliorated
by MeCbl (22,23) (Table 1). The effects of single
use of MeCbl or combined use with other drugs
were examined in diabetic neuropathy pain (13,
24) (Table 1). Clinical evidence showed that MeCbl
had the ability to inhibit the neuropathic pain
accompanying diabetic neuropathy.
Table 1: The analgesic
effect of MeCbl or combined use with other drugs
on patients with diabetic neuropathic pain
The severity of the pain is variable and may
be explained as a hot, burning, cold, aching,
or itching sensation with, at times, increased
skin sensitivity. It is a challenge in clinical
practice to treat diabetic neuropathic pain. Several
medications have been tried including Carbamazepine,
and dolantin with no success. Similarly, therapeutic
effects of aldose reductase inhibitors and nimodipine
were not promising in clinic as much as basic
studies showed. Fortunately, MeCbl may convey
a sparkle of hope to treat diabetic neuropathic
pain.
2.2. Low Back Pain
Back pain is one of the most frequent health complaints.
It is a common complaint affecting 70-85% of people
worldwide at some point during their life (25).
The differential is extensive including, cancer,
infection, inflammatory disorders, structural
disorders of the spine itself, and disk herniation,
are somewhat more common, and together account
for back pain.
According to the WHO (World Health Organization),
low back pain leads to a high economic burden
due to the effects this often chronic problem
has on work productivity (26). It is one of the
most frequent causes behind visiting a primary
care provider, and in the top five of the most
common reasons for having surgery(27).
Initially, low back pain is usually
managed with anti-inflammatories including non-steroidal,
muscle relaxants, and narcotics. Persistent back
pain is further treated with physical therapy,
TENS units, massage, epidural steroid injections,
and surgery. Treatment varies depending on the
patient. The majority of patients recover within
12 weeks, while 10 to 20% endure low back pain
past this time period, even with treatment (27,28).
It emerges that vitamin B12 might be one of those
additional treatment options.
The advantage of using B12 shots
included decreasing the amount of non-steroidal
anti-inflammatory drugs (NSAID), such as aspirin
and ibuprofen. Vitamin B12 has no known side effects,
according to the National Institutes of Health
Office of Dietary Supplements, rivaled to long-term
NSAID use, which may harm the gastrointestinal
system and probably lead to heart attacks and
strokes. Researchers aren't sure how vitamin B12
shots help patients decrease back pain. However,
they anticipate that the vitamin helps nerves
repair and regenerate in the back. Additional
benefits to treating back pain with B12 shots
include the vitamin's low cost, minimal side effects,
and ability to get patients back to work and enjoying
their lives.
Furthermore neurogenic claudication
distance was ameliorated markedly after the application
of MeCbl [29] (Table 2). However Waikakul's research
showed that MeCbl was not good for pain on lumbar
spinal stenosis [29]. In a trial, the analgesic
effect of MeCbl has been examined in nonspecific
low back pain patients with intramuscular injection
[30] (Table 2). The varying effect of MeCbl may
be secondary to different causes of lumbar spinal
stenosis and nonspecific low back pain. Additional
studies are required to establish the effect of
MeCbl on low back pain.
Three studies
Studies have shown that vitamin B12 shots can
successfully decrease back pain.
One study conducted in 2000 by Italian researchers
at the University of Palermo found that vitamin
B12 helped to alleviate lower back pain. The study
evaluated 60 patients aged between 18 and 65 with
proven back pain lasting anywhere from six months
to five years.
Study participants were divided into two groups
and received either a B12 shot or a placebo. Results
showed injections alleviated back pain in patients
even if they entered the study with adequate blood
levels of vitamin B12.
CHIU et al (31) conducted a randomized,
double-blinded, placebo control study (5) to evaluate
both the efficacy and safety of intramuscular
methylcobalamin injections for treatment of chronic
low back pain. Certain eligibility
criteria were used for selection of the patient
population. Included were patients who were between
20 and 65 years old and who had a history of low
back pain, which had to be nonspecific in nature,
and for greater than 6 months in duration. At
the study's conclusion neither disability nor
pain was meaningfully reduced in the
placebo group. However, in the treatment group
they established a marked decrease in both disability
and pain. These inferences were based on the ODI
and VAS scores taken 2 months after initiation
of treatment, see Table 2. Furthermore, the placebo
group consumed significantly higher doses of paracetamol
as compared to the participants in the treatment
group; mean paracetamol consumption (in grams)
was 87.6 ± 57.3 in the
placebo group, 65.7 ± 75.2 in the treatment
group. Treatment with intramuscular (IM) methylcobalaminhad
very few side effects, including hematoma and
pain at the injection site. It is difficult to
estimate any long term side effects since the
duration of the study was short, 2 months.
MAURO et al (32) using a randomized,
double blinded, placebo control study studied
the efficacy of vitamin B12 in treating low back
pain. Patients ranged between 18 to 65 years old
with medical evidence of 6 months to 5 years of
mechanical low back pain or sciatic neuritis.
They also had to have at least 60 out of 100 on
the VAS
pain intensity scale at the start of the study.
The total patients included were 60 patients.
They were randomly allocated to either the placebo
or the treatment group. The treatment group received
Tricortin® 1000 2mL ampoulescontaining 1000
mg vitamin B12, whereas the placebo group only
received 2 mL ampoules of an unspecified injection.
Pain was evaluated with the VAS,
a test in which the participants scored their
pain on a scale of 0-100, where 0 meant no pain
at all, and 100 was the worse pain one can have.
In addition the use of paracetamol was used to
assess pain. Disability was assessed by using
the DQ, a test that is made up of 24 questions
and is then scored on a 0-24 scale. In both the
placebo and treatment group Pain and disability
improved. In the placebo
group the VAS score declined from 70.63 ±
7.9 to 36.83 ± 27.4, whereas in thetreatment
group it declined from 75.53 ± 8.9 to 9.53
± 16.5. The DQ score decreased from 11.53
± 2.2 to 5.80 ± 3.3 in the placebo
group and it decreased from 13.27 ± 2.7
to 2.43 ± 2.6 in the treatment group.
Nevertheless, there was a more
statistically significant improvement in the treatment
group. Paracetamol was used less in the treatment
group. There were no reported adverse effects.
Therefore IM injection of vitamin B12 is safe
in the short term. However, long term effects
of IM injections of vitamin B12 were not examined
nor discussed in this study.
A study from Lebanon (33) examined
the usefulness of cobolamin injection in lumbosacral
disc disease in patients with mechanical or irritative
lumbago. Over 4 years a hundred and twenty patients
with Lumbosacra l disease were enrolled in the
study. Patients' ages ranged between 18 to 65
years. The patients were divided randomly into
treatment and control group. Both groups received
relative bed rest, NSAID's and daily injection
of vitamin B12 for the treatment group and sterile
water for the control group. The duration of treatment
lasted for three weeks, and the concentration
of vitamin B12 was 1000 mg/ml. Patients were seen
initially and at the end of treatment. Both treatment
groups experienced a sharp decrease in pain and
disability. However, comparison between groups
at the end of the treatment period showed a statistically
significant difference in favour of the active
treatment both for pain, paraesthesia, and nocturnal
pain. Consumption of paracetamol proved significantly
higher in the placebo group than in the active
treatment (p < 0.0001). The author concluded
that Intramuscular vitamin B12 injections seem
to be effective at ameliorating nonspecific chronic
low back pain as compared to placebo. Vitamin
B12 injections also have exhibited only minimal
side effects. There is a need for a larger study
with longer duration that spans several years
to assess the long term side effects, especially
as long term effects can possibly be serious.
2.3. Neck Pain
Chronic neck pain is becoming
a common problem in the adult population, with
the prevalence of 30%-50% in 12 months [34, 35].
It was shown that spontaneous pain, allodynia,
and paraesthesia of patients with neck pain were
improved significantly in the MeCbl group, and
with the increase of treatment time of MeCbl,
the analgesic effect was more obvious [36] (Table
2).
Table 2: The analgesic
effects of MeCbl on low back pain and neck pain
in clinical trials
2.4. Neuralgia
2.4.1. Subacute Herpetic Neuralgia
The use of
MeCbl markedly decrease unremitting pain, paroxysmal
pain, and allodynia in the subacute herpetic neuralgia
(SHN) patients (37) (Table 3). Therefore, Vitamin
B12 can be used as an adjuvant treatment for SHN.
Table 3: The analgesic effect
of MeCbl or combined with other agents on neuralgia
2.4.2. Glossopharyngeal Neuralgia
In pain clinics Glossopharyngeal neuralgia (GPN)
is common. It was stated that the numerical pain
scales were reduced markedly with the treatment
of MeCbl combined with gabapentin and tramadol
in GPN patients (38) (Table 3). In addition the
quality of life improved markedly (38).
2.4.3. Trigeminal Neuralgia
The pain of trigeminal neuralgia (TN) can be portrayed
as excruciating, paroxysmal and lancinating which
may be activated by minor deeds such as chewing,
speaking, and swallowing. A recent study showed
that the pain of TN patients was eased significantly
in the MeCbl group, and no recurrence of TN in
64% of the cases(39) (Table 3).
Since many decades, the B12 group
of vitamins had been used to treat pain. In some
countries, vitamin B12 was labeled as an analgesic
drug. It was implied that vitamin B12 may augment
the availability and effectiveness of noradrenaline
and 5-hydroxytryptamine in the descending inhibitory
nociceptive system (40). MeCbl has therapeutic
effects on neuropathic pain in diabetics, conceivably
through its neurosynthesis and neuroprotective
actions (14, 41). However the analgesic mechanisms
of MeCbl continue to be obscure. There are
three sets of speculation on that matter below.
3.1. Improving Nerve Conduction
Velocity
Several authors revealed that high doses of MeCbl
amended nerve conduction in either patients with
diabetic neuropathy (13-15), streptozotocin-diabetic
rats (16), or experimental acrylamide neuropathy
(17). Morphological and histological evidence
established that a long-term administration of
MeCbl stimulated the synthesis and regeneration
of myelin (42). These morphological and histological
recoveries of myelin can lead to ameliorating
nerve conduction velocity and neuronal function
in peripheral neuropathy.
3.2. Promoting the Regeneration
of Injured Nerves
In vivo MeCbl advanced the incorporation of radioactive
leucine into the protein fraction of the crushed
sciatic nerve. Therefore, this led to the recovery
of the injured nerve activity (43). In this study,
most terminals were degenerated in the mutant
mouse, but the sprouts were more often observed
in the MeCbl treatment group (44). MeCbl had the
power to support the injured nerves' regeneration.
In the experimental acrylamide neuropathy and
sciatic nerve injury models, the number of regenerations
of motor fibers showed significant increase with
high-dose methylcobalamin (17). In addition, the
combined use of L-methylfolate, MeCbl, and pyridoxal
5?-phosphate ameliorate the calf muscle surface
neural density (45).
3.3. Inhibiting Ectopic Spontaneous
Discharge
Ectopic spontaneous discharges are possible to
start spontaneous pain, hyperalgesia, and allodynia
(46-49). It was reported that MeCbl suppressed
the ectopic firing triggered by chemical materials
in the dog dorsal root (50).
Chronic pain is a usual complaint,
leading the sufferer to be up to five times more
likely to pursue medical
attention as compared to those people without
chronic pain (8). Lumbago, is a main cause of
chronic pain. Within a year period one third of
patients with this pain will experience lumbago
(28). It has also been projected that around 80%
of people will have low back pain at some point
during their life (27). The bulk of low back pain
(90%) without related neurological symptoms improves
within 3 months (51). The remaining 10% are a
challenge to many healthcare providers, not only
because chronic low back pain is challenging to
manage, it is also normally linked to anxiety,
depression, job dissatisfaction, poor body image
and somatization (28)
The therapeutic options for low
back pain include NSAIDs, tramadol acetaminophen
combinations, non-SSRI antidepressants, and glucocorticoids
or local anesthetic to = the spine (52). These
medications may lead to serious side effects,
particularly when used for long periods of time.
NSAIDS, for example can lead to kidney dysfunction,
acetaminophen can cause liver dysfunction and
glucocorticoids can cause weight gain, insomnia,
and Cushing syndrome. Studies revealed that out
of the available treatments only NSAIDs seem to
ameliorate function (52). Recent studies (31,32,33)
have shown that injectable cobalamin might also
be a promising treatment option for lumbago.
Several studies (53-59), have
suggested that large doses of vitamin B12 in combination
with NSAIDs may lead to heightening effect on
the analgesic properties of NSAIDs, therefore
possibly decreasing NSAID dosing.
Vitamin B12 is mostly used for
treatment of deficiency, which is often due to
malabsorption, insufficient dietary intake, pernicious
anemia, gastric surgery, GI disease, and particular
medications (60). If longterm effects of vitamin
B12 injection show to be safe, vitamin B12 might
be a precious treatment alternative for low back
pain. This will be particularly important for
the elderly, for patients prone to liver or kidney
disease or people interested in natural substance.
The three randomized clinical trials (31-33) revealed
that vitamin B12 compared to placebo, decreases
low back pain and improves function significantly.
However these studies have limitations, including
small size that leads to large confidence intervals
that the possibility that treatment effect was
not precise. In addition none of the studies investigated
the longterm effects of injectable vitamin B12.
It is known that high serum levels of vitamin
B12 are linked to cancer, liver, renal, and inflammatory
diseases (61). In one study vitamin B12 serum
levels of >1275 pg/mL were associated with
hematologic malignancies (62). Therefore, it is
important to consider the possible side effects
associated with long term risk. Studies that evaluate
longterm effects of high serum cobalamin levels
had their limitations. In one study the age of
the patient was important in determining the level
of vitamin B12 where the older patients had a
higher level (63).
It is known that elderly have
multiple comorbidities. Hence it was challenging
to attribute the results of the study to the vitamin
B12 levels versus the participants age (64). One
more limitation is the fact that vitamin B12 was
the only lab value looked at for its possible
relation to cancer development (65). Other electrolyte
abnormality
or vitamin deficiency may be implicated for the
cause for an increased risk of cancer.
In addition we are not sure that
the cobalamin doses used in the treatment of low
back pain were high enough to lead to high serum
vitamin B12 levels discussed (63,64).
Although vitamin B12 seems
to have significant benefit in the treatment of
chronic low back pain, further research, with
elimination of some of these limiting factors,
is needed to study whether the intramuscular vitamin
B12 injection doses are indeed harmful in the
long run.
Intramuscular vitamin B12 injections
seem to be effective at ameliorating nonspecific
chronic low back pain as compared to placebo.
Vitamin B12 injections also have exhibited only
minimal side effects, which include hematoma and
pain at the injection site.
There is a need for larger study with longer duration
that spans several years to assess the longterm
side effects. Especially that longterm effects
can be possibly serious. Meanwhile, physicians
may use vitamin B12 treatments in addition to
established treatment to prudently selected patients.
MeCbl or its joint use with other
agents has the conceivable analgesic effect in
specific patients and animal models, for example,
nonspecific low back pain; neck pain; diabetic
neuropathic pain, subacute herpetic neuralgia,
glossopharyngeal neuralgia, and trigeminal neuralgia.
However, the mechanisms underlying the analgesic
effect were badly comprehended. On the basis of
recent work, the likely mechanisms can be considered
as follows. (1) MeCbl improved nerve conduction
velocity; (2) MeCbl promoted injured nerve regeneration,
recovering the neuromuscular functions in peripheral
hyperalgesia and allodynia; and (3) MeCbl inhibited
the ectopic spontaneous discharges from peripheral
primary sensory neurons in neuropathic pain states.
Therefore, MeCbl can be used for treating peripheral
neuropathy with good safety.
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