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Carr and McCall J Transl Med (2017) 15:77
DOI 10.1186/s12967-017-1179-7
REVIEW
The role ofvitamin C inthe treatment
ofpain: new insights
Anitra C. Carr1* and Cate McCall2
Abstract
The vitamin C deficiency disease scurvy is characterised by musculoskeletal pain and recent epidemiological evi-
dence has indicated an association between suboptimal vitamin C status and spinal pain. Furthermore, accumulating
evidence indicates that vitamin C administration can exhibit analgesic properties in some clinical conditions. The
prevalence of hypovitaminosis C and vitamin C deficiency is high in various patient groups, such as surgical/trauma,
infectious diseases and cancer patients. A number of recent clinical studies have shown that vitamin C administration
to patients with chronic regional pain syndrome decreases their symptoms. Acute herpetic and post-herpetic neu-
ralgia is also diminished with high dose vitamin C administration. Furthermore, cancer-related pain is decreased with
high dose vitamin C, contributing to enhanced patient quality of life. A number of mechanisms have been proposed
for vitamin C’s analgesic properties. Herein we propose a novel analgesic mechanism for vitamin C; as a cofactor for
the biosynthesis of amidated opioid peptides. It is well established that vitamin C participates in the amidation of
peptides, through acting as a cofactor for peptidyl-glycine α-amidating monooxygenase, the only enzyme known to
amidate the carboxy terminal residue of neuropeptides and peptide hormones. Support for our proposed mecha-
nism comes from studies which show a decreased requirement for opioid analgesics in surgical and cancer patients
administered high dose vitamin C. Overall, vitamin C appears to be a safe and effective adjunctive therapy for acute
and chronic pain relief in specific patient groups.
Keywords: Vitamin C, Chronic regional pain syndrome, Post-herpetic neuralgia, Cancer quality of life,
Opioid requirements
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Background
Pain is defined as ‘an unpleasant sensory and emotional
experience associated with actual or potential tissue
damage, or described in terms of such damage’ [1]. e
taxonomy of pain has developed through the work of
the International Association for the Study of Pain and
encompasses broad classifications that relate to the aeti-
ology of pain, such as nociceptive (pain in response to
injury) and neuropathic (nerve pain or pain in response
to nerve damage), as well as particular pain features, such
as allodynia (increased sensitization of neurons) and
hyperalgesia (increased sensitivity to pain). Time course
influences, such as chronic and acute, are also taken into
consideration. e principal organ of pain is the brain.
Noxious stimuli, once transduced, are conducted as noci-
ceptive signals to the central nervous system via the spi-
nal cord and ascend to the higher centres. It is here that
the experience of pain is perceived and experienced in a
complex and dynamic interaction between cerebral areas
both sophisticated and primal. Pain is a transdiagnostic
symptom and while somatic pathology plays a role in
activating pain pathways, psychosocial, cultural and envi-
ronmental factors influence the experience of pain over
time [2].
In the absence of empirical evidence to validate the
presence of pain measurement relies largely on elicit-
ing the experience of the patient through self-report. It
is understood that pain is an individual and subjective
experience and may or may not be associated with evi-
dent tissue damage or disease. Furthermore, there are
many influencing factors, such as mental state (both
Open Access
Journal of
Translational Medicine
*Correspondence: anitra.carr@otago.ac.nz
1 Department of Pathology, University of Otago, Christchurch,
PO Box 4345, Christchurch 8140, New Zealand
Full list of author information is available at the end of the article
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Carr and McCall J Transl Med (2017) 15:77
organic and psychological), coping strategies, social/cul-
tural context, experience, and co-symptoms. e patient
self-report can be validated using multiple outcome
measurement tools designed to capture the complexity of
the pain experience, for example, the visual analogue and
numerical pain rating scales [3], the McGill pain ques-
tionnaire [4], and the Brief Pain Inventory [5].
Recent epidemiological evidence has indicated an
association between spinal pain and suboptimal vitamin
C status [6]. Musculoskeletal pain is also a symptom of
the vitamin C deficiency disease scurvy [7]. Further-
more, accumulating evidence indicates that vitamin C
administration can exhibit analgesic properties in some
clinical conditions. In this review we focus on human
studies investigating the role of vitamin C in orthope-
dic, virus-associated, cancer-related, and post-surgical
pain. Preclinical models of pain are not always directly
comparable to clinical scenarios of pain [8]. Neverthe-
less, we discuss some preclinical studies, although these
have been carried out in animals that can synthesise their
own vitamin C and, as such, are not ideal models for the
human vitamin C-requiring situation. Vitamin C has a
number of important functions in the body, primarily
through acting as a cofactor for a family of biosynthetic
and regulatory metallo-enzymes. ese functions include
synthesis of neurotransmitters and peptide hormones,
and regulation of transcription factors and gene expres-
sion [9, 10]. We cover the potential analgesic mechanisms
of vitamin C and propose a novel analgesic mechanism
involving the biosynthesis of amidated opioid peptides.
We also discuss study limitations, highlighting the need
for an improved understanding of the pharmacokinetics
of oral and intravenous vitamin C in future studies.
Vitamin C deciency andpain
Pain is a symptom of the vitamin C deficiency disease
scurvy, presenting primarily within the musculoskeletal
system as arthralgia in the knees, ankles and wrists, as
well as myalgia [7, 11]. Children in particular suffer from
severe lower limb pain, as evidenced by numerous case
reports in the literature [12–16]. ere have also been
reports of adults and the elderly experiencing musculo-
skeletal pain due to severe vitamin C deficiency [17, 18].
Scurvy-related pain appears to be primarily due to bleed-
ing into the musculoskeletal tissues, which can become so
debilitating that patients are unable to walk [7]. Bleeding
into the muscles and other soft tissues results in swelling
and tenderness in the affected area, whilst bleeding into
the hip, knee and ankle joints results in hemarthroses,
and bleeding into the periosteum results in severe bone
pain. Pain due to vitamin C deficiency can be completely
resolved within a week or two following supplementation
with intakes of vitamin C that will eventually result in
plasma saturation (i.e.≥200mg/day, see examples cited
in [12]).
It is interesting to note that Duggan etal. reported that
a child’s painful scurvy symptoms began after an upper
respiratory infection and that “possibly the increased
metabolic needs associated with this infection unmasked
a subclinical vitamin C deficiency [14].” Khalid also
reported three cases of children suffering from respira-
tory infections or gastrointestinal dysfunction who con-
currently developed painful swellings of their joints [16].
e author stated that “scurvy occurred as a result of
their increased requirement of vitamin C due to stress of
illness combined with poor dietary intake. It is therefore
recommended that during illness one should be careful
about the intake of vitamin C, keeping in mind that acute
illness rapidly depletes stores of ascorbic acid. ose
already malnourished are more prone to this develop-
ment [14].” Similarly, others have reported painful scurvy
symptoms following confirmed or suspected respiratory
infection [18, 19], stating that “sepsis of either digestive
or pulmonary origin, leading to sustained metabolic
demand, might have acted as a precipitating factor [18].”
As such, it is possible that other hospital-associated pain
may be partly due to vitamin C deficiency, which is rela-
tively prevalent in hospital settings [20–23].
Vitamin C deciency andenhanced requirements
inpatients
Vitamin C deficiency (defined as plasma vitamin C con-
centrations<11µmol/L) is relatively rare in the general
population of developed countries, with a prevalence
of 6% reported in the United States [24]. However, vita-
min C deficiency and scurvy has been reported to occur
in elderly hospitalized patients [25, 26], critically ill
patients [18, 27, 28], and cancer patients [29]. Hospital-
ized patients, in general, are more likely to present with
hypovitaminosis C (defined as plasma vitamin C concen-
trations<23µmol/L), and a higher proportion of hospi-
tal patients exhibit deficiency compared with the general
population [20, 21]. Trauma and surgery are known to
significantly deplete vitamin C concentrations [22], and
patients with severe infections and sepsis also have sig-
nificant depletion of vitamin C [23]. Cancer patients typi-
cally have lower vitamin C status than healthy controls
[30, 31], with a large proportion of them presenting with
hypovitaminosis C and outright deficiency [32].
It is interesting to note that animals, which can syn-
thesise their own vitamin C, will increase their synthe-
sis of the vitamin if they become stressed, are under a
disease burden, or are administered drugs, including
analgesics [33–35]. erefore, it seems likely that hos-
pitalised patients, who are under enhanced physiologi-
cal stress, often presenting with a disease burden, and
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Carr and McCall J Transl Med (2017) 15:77
being administered multiple drugs, will have enhanced
requirements for vitamin C. In support of this premise,
vitamin C intakes of 100–200mg/day provide adequate
to saturating plasma status in healthy individuals [36],
however, much higher gram doses are required to nor-
malize plasma vitamin C status in surgical and critically
ill patients [22, 23]. Administration of vitamin C to can-
cer patients results in lower plasma concentrations com-
pared with healthy controls [37], suggesting a depleted
body pool. Furthermore, administration of some anti-
cancer therapies has been shown to significantly decrease
patient vitamin C concentrations and scurvy-like symp-
toms have been reported [38–40]. Other drugs, such as
aspirin, may also interfere with vitamin C uptake and
could potentially result in hypovitaminosis C in individu-
als with low vitamin C intake [41]. Overall, these studies
indicate an increased utilisation of and requirement for
vitamin C in different patient cohorts.
Vitamin C andorthopedic pain
Persistent musculoskeletal pain and associated com-
plex regional pain syndrome (CRPS) present particular
features underpinned by complex dynamic neural plas-
ticity [3]. Features such as allodynia and hyperalgesia
allude to sensitization of the nociceptive neurons, both
peripheral and central, which invokes a cascade of effects
experienced as pain that is both difficult to predict and
manage. Vitamin C deficiency has been associated with
spinal pain, primarily neck, lower back and arthritis/
rheumatism [6]. e vitamin has been shown to exert a
number of regulatory effects on cells of the skeletal sys-
tem, including osteogenic, chondrogenic and osteoblas-
togenic [42]. Mechanisms of vitamin C action in bone
cells primarily involve up- or downregulation of the
expression of specific genes through regulation of tran-
scription factors and epigenetic marks.
A number of randomized controlled trials have inves-
tigated the effect of vitamin C supplementation on the
incidence of CRPS in wrist and ankle surgery patients
(Table1) [43–47]. Doses of vitamin C used in these stud-
ies ranged from 0.2 to 1.5 g/day for 45–50 days post-
surgery. All studies, but one [43], showed a decreased
incidence of CRPS in the patients receiving vitamin
C, with vitamin C doses ≥0.5 g/day being the most
Table 1 The eect ofvitamin C oncomplex regional pain syndrome (CRPS) andother orthopedic pain
IV intravenous, VAS visual analog scale, QLQ quality of life questionnaire
*P<0.05
a Study was included in CRPS meta-analysis [48–52]
Study type Intervention Findings
Placebo controlled RCT
Wrist fractures [43]ai. Placebo (N = 167) i. 20–42% CRPS (at 6 weeks), 5–16% CRPS (at 1 year)
ii. 500 mg/day oral vitamin C (N = 169) for 50 days ii. 40–42% CRPS (at 6 weeks), 6–16% CRPS (at 1 year)
Wrist fractures [44]ai. Placebo (N = 99) i. 10% CRPS
ii. 200 mg/day oral vitamin C (N = 96) ii. 4% CRPS
iii. 500 mg/day oral vitamin C (N = 144) iii. 2% CRPS*
iv. 1.5 g/day oral vitamin C (N = 118) for 50 days iv. 2% CRPS*
Wrist fractures [45]ai. Placebo (N = 63) i. 22% CRPS
ii. 500 mg/day oral vitamin C (N = 52) for 50 days ii. 7% CRPS* (at 1 year follow up)
Hip/knee osteoarthritis [55] Placebo or 1 g/day oral vitamin C (N = 133)
Cross-over design, 14 days with 7 day washout 5% ↓ pain (VAS)*
Controlled prospective
Foot and ankle surgery [46]ai. Control (N = 235) i. 10% CRPS
ii. 1 g/day oral vitamin C (N = 185) for 45 days ii. 2% CRPS*
Wrist fracture surgery [47]ai. Control (N = 100) i. 10% CRPS
ii. 1 g/day oral vitamin C (N = 95) for 45 days ii. 2% CRPS* (at 90 day follow up)
Paget’s disease of bone [59] i. Calcitonin (N = 13) i. Pain relief in 85%, marked ↓ pain in 31%
ii. Calcitonin + 3 g/day vitamin C (N = 11) for 2 weeks ii. Pain relief in 73%, marked ↓ pain in 45%
Uncontrolled prospective
Arthritic joint replacement surgery [54]a500 mg/day oral vitamin C (N = 34) for 50 days 0% CRPS cases
Paget’s disease of bone [58] 3 g/day oral vitamin C (N = 16) for 2 weeks ↓ Pain in 50%, no pain in 20% (within 5-7 days)
Case report
Rheumatoid arthritis [56] 50 g IV vitamin C twice/week for 4 weeks Before: 100% pain (QLQ)
After: 0% pain
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Carr and McCall J Transl Med (2017) 15:77
efficacious [44]. Previous research has indicated that
surgical patients have high vitamin C requirements and
supplementation with>0.5 g/day vitamin C is required
to restore normal vitamin C status in these patients [22].
e results of these studies have been pooled in vari-
ous combinations in a number of recent meta-analyses
[48–52] and all, but one [50], concluded that the evidence
indicates that daily administration of vitamin C can
decrease the incidence of CRPS following distal fracture
surgery.
Patients undergoing joint replacement surgery for
osteoarthritis were administered 0.5 g/day prophylac-
tic vitamin C for 50days post-surgery (Table1) [53, 54].
Although osteoarthritis of the carpometacarpo joint
can be complicated by CRPS, no cases of CRPS were
observed under vitamin C prophylaxis. A randomized
placebo-controlled crossover trial carried out with
133 patients with osteoarthritis of the hip or knee joint
showed reduced pain following consumption of 1g/day
calcium ascorbate for 2weeks as determined by the visual
analogue scale (P<0.008) [55]. e observed decrease in
pain was less than half that reported for non-steroidal
anti-inflammatories. We have shown a complete decrease
in pain in a patient with rheumatoid arthritis following
administration of twice weekly infusions of high-dose
vitamin C [56]. is data suggests that vitamin C may be
more effective for the pain associated with rheumatoid
arthritis than osteoarthritis, or that intravenous admin-
istration of the vitamin may be more effective than oral
administration in patients with arthritis. It is noteworthy
that the average vitamin C status of patients with rheu-
matoid arthritis is less than half that of healthy controls
(i.e. 27±13 versus 70±21µmol/L, respectively) [57].
Paget’s disease of bone is a chronic disorder caused
by the excessive breakdown and formation of bone and
disorganized bone remodeling which results in bone
weakening, misshapen bones, fractures, arthritis, and
pain. An early study in 16 patients with Paget’s dis-
ease of bone showed that oral doses of 3g/day vitamin
C for 2weeks decreased pain in 50% of the patients and
resulted in a complete elimination of pain in 20% of the
patients [58]. Excretion of hydroxyproline was elevated
following administration of vitamin C, and was high-
est in those patients who experienced complete relief of
pain. is suggests that vitamin C is acting as a cofactor
for the hydroxylase enzymes responsible for collagen syn-
thesis [10]. When 3g/day vitamin C was administered
to Piaget’s patients in combination with normal calci-
tonin treatment, there was no additional attenuation of
pain above calcitonin alone, although normalization of
hydroxyproline excretion was observed, in contrast to
calcitonin treatment, which decreases hydroxyproline
excretion [59].
Vitamin C andvirus‑associated pain
Infection with viral pathogens is commonly associated
with myalgia, arthralgia or neuralgia [60]. Herpes zoster
infection (shingles) results in a painful skin rash which
generally lasts 2–4weeks. However, some people develop
ongoing nerve pain, a condition known as postherpetic
neuralgia, which may last for months or years and is
due to nerve damage or alterations caused by the virus
in discrete dermatomes. Pain can be mild to extreme in
the affected dermatome, and can include sensations of
burning pain, itching, hyperesthesia (oversensitivity),
or paresthesia (tingling, pricking, or numbness, ‘pins
and needles’) [61, 62]. Analysis of the nutrient status of
50 patients with postherpetic neuralgia indicated sig-
nificantly lower circulating concentrations of vitamin
C compared with 50 healthy controls (i.e. 30±21 ver-
sus 76± 31µmol/L, respectively) [63]. More than 50%
of the patients had hypovitaminosis C (i.e.<23 µmol/L)
and vitamin C concentrations≤45µmol/L were found to
independently increase the risk of post-herpetic neural-
gia (adjusted OR 21; 95% CI 6, 76; P<0.001).
A number of case studies have indicated that both
acute and postherpetic neuralgia can be dramatically
decreased following intravenous vitamin C infusions
(2.5–15g daily or every other day for 5–14days) [64–
67]. In an uncontrolled follow-up study, Schencking
etal. recruited 64 patients with Herpes Zoster who were
subsequently administered 7.5 g intravenous vitamin
C two to four times a week for a total of 2weeks [68].
Baseline pain was reported to be 58% (as determined
by VAS), which decreased to 22% within 2weeks and
this had decreased to 6% at 12week follow-up. Over-
all, there was a decrease in pain for 92% of the patients.
e lack of a control group is a major limitation of this
study.
Two placebo-controlled trials have investigated the
effect of intravenous vitamin C on acute and post-her-
petic neuralgia (Table 2) [69, 70]. Chen et al. carried
out a trial in 41 patients with postherpetic neuralgia
randomized to receive intravenously 50mg vitamin C/
kg body weight three times over 5days, or placebo infu-
sion [69]. Patients receiving vitamin C reported a larger
decrease in numeric rating scale for pain, and a greater
global impression of change. Another recent RCT in 87
herpes zoster patients, randomized to receive 5g intrave-
nous vitamin C or placebo three times over 5days, found
no effect on acute pain within the first 4weeks of hos-
pitalization, but did show a decreased incidence of pos-
therpetic neuralgia and significantly decreased pain at 8
and 16weeks follow up [70].
Chikunguya virus infection is characterized by severe
joint pain, which typically lasts weeks or months, and
sometimes years [71]. Parvovirus B19 infection (also
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Carr and McCall J Transl Med (2017) 15:77
known as fifth disease) may also present with acute or
persistent arthropathy, painful swelling of the joints
that feels similar to arthritis [72]. Two cases of severe
arthralgia associated with Chikungunya and parovirus
B19 reportedly responded to high dose oral (10 g/day)
and intravenous vitamin C treatments (Table2) [73, 74].
Despite one case having 100g/day vitamin C infusions,
no adverse side effects were reported [73]. An uncon-
trolled prospective study carried out in 56 patients with
Chikungunya virus indicated that a single infusion of
25–50g intravenous vitamin C (administered with a 3%
hydrogen peroxide solution) provided a 60% decrease in
pain and completely eliminated pain in 9% of the patients
[75].
Vitamin C andcancer‑related pain
Pain is one of the most common symptoms reported by
cancer patients, and can seriously affect their quality of
life [76]. Pain associated with cancer can be related to the
primary tumour, cancer treatment, associated procedures
and as a consequences of disease progression and metas-
tasis. Furthermore, cancer pain may include several types
of pain and pain features occurring concurrently as mixed
pain, such as nociceptive, neuropathic, and bone pain
[3]. Cancer-associated pain resulting from metastasis to
bone is a severe and complex condition comprising neu-
ropathic, nociceptive and inflammatory pain [77, 78]. As
mentioned above, cancer patients typically have depleted
vitamin C status [30–32] as well as higher requirements
Table 2 The eect ofvitamin C onacute andchronic viral-associated pain
IV intravenous, NAS numerical analogue scale, NRS numeric rating scale, PCIG patient global impression of change, PHN postherpetic neuralgia, VAS visual analogue
scale
*P<0.05
Study type Intervention Findings
Placebo controlled RCT
Herpes Zoster [70] i. Placebo infusion (N = 42) i. 4.2 ↓ VAS, 57% PHN incidence
ii. 5 g IV vitamin C (N = 45) on days 1, 3, 5 ii. ≥5.6 ↓ VAS*, 31% PHN incidence* (at 8 and
16 week follow up)
Postherpetic neuralgia [69] i. Placebo infusion (N = 20) i. 0.9 ↓ NRS, 10% PGIC
ii. 50 mg IV vitamin C/kg body weight (max dose
2.5 g/day) (N = 21) three times over 5 days ii. 3.1 ↓ NRS*, 62% PGIC* (at 7 day follow up)
Uncontrolled prospective
Herpes Zoster [68] 7.5 g IV vitamin C (N = 64) 2–4 times/week for
2 weeks Baseline: 58% pain (VAS)
Week 2: 22% pain
Week 12: 6% pain
Chikungunya virus—moderate to severe pain
[75]H2O2 + 25–50 g IV vitamin C (N = 56) single
infusion Before: 80% pain (NRS)
After: 20% pain, no pain in 9% of patients
Case report
Parvovirus B19 viremia—chronic arthralgia [74] i. 10 g/day oral vitamin C for 10 days i. Before: 30% pain (VAS)
After: 5% pain
ii. 10 g/day oral vitamin C for 3 weeks ii. Before: 40% pain (VAS)
After: 10% pain (at 3–5 week follow up,
there was↓ pain within 5 days)
Chikungunya virus—severe joint pain [73] 100 g/day IV vitamin C for 2 days Pain resolved within 24 h
Refractory herpes zoster-associated pain [67] 4 g/day IV vitamin C for 5 days Before: 70% pain (VAS)
After: 0% pain (at 3 month follow up)
Herpes zoster—severe dermatological pain [66] Cantharidin + 7.5 g IV vitamin C every 2 days for
2 weeks Before: 80% pain (NAS)
After: 40% pain (within 2 weeks),
0% pain (at 8 week follow up)
Acute herpetic neuralgia [65] 15 g IV vitamin C every 2 days for 12 days Before: 80% pain (VAS)
After: 0% pain (within 8 days)
Acute herpetic neuralgia [65] 15 g IV vitamin C every 2 days for 16 days Before: 100% pain (VAS)
After: 0% pain (within 12 days)
Postherpetic neuralgia [64] 2.5 g IV vitamin C every 2 days for 5 days Before: 73% pain (NRS)
After: 0% pain (within 7 days and at 3 month
follow up)
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Carr and McCall J Transl Med (2017) 15:77
than healthy controls [37], which could potentially be
exacerbated by anti-cancer therapies [38–40].
High dose oral and intravenous vitamin C has been
administered to cancer patients for many decades as a
complementary and alternative therapy [79]. Although
the efficacy of vitamin C as a cancer treatment is ques-
tionable, recent research has indicated a positive impact
of high dose vitamin C on cancer- and chemotherapy-
related quality of life, including pain [80]. Early stud-
ies of high dose vitamin C in patients with advanced
cancer indicated that many patients experienced
some improvement in subjective symptoms, includ-
ing decreased pain and the need for analgesics [81, 82].
Cameron and Campbell [81] reported a number of cases
of dramatic to complete amelioration of bone pain in
patients with severe cancer-related pain given both high
dose oral and intravenous vitamin C (Table3). Retro-
spective studies of patients with bone metastases receiv-
ing 2.5g intravenous vitamin C once weekly or during
intensifying pain reported a range of responses, including
0–100% decreases in pain [83, 84]. ese, and the earlier
case studies [81], indicate that vitamin C can potentially
Table 3 The eect ofvitamin C oncancer-related pain
EORTC QLQ European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire, IV intravenous, VAS visual analogue scale
*P<0.05
Study type Intervention Findings
Uncontrolled prospective
Advanced cancer [90] 0.8–3 g IV vitamin C/kg body weight (N = 17)
4 days/week for 4 weeks Before: 36% pain (N = 17)
Week 1: 35% pain (N = 16)
Week 2: 35% pain (N = 12)
Week 3: 29% pain (N = 7)
Week 4: 0% pain (N = 2)
(EORTC QLQ)
Advanced cancer [89] 25–100 g IV vitamin C (N = 60) twice weekly for
4 weeks Before: 18% pain
Week 2: 14% pain
Week 4: 10% pain
(EORTC QLQ)
Terminal cancer [88] 10 g IV vitamin C (N = 39) twice over 1 week 4 g/
day oral vitamin C for 1 week Before: 30% pain
Week 1: 21% pain
(EORTC QLQ)
Controlled retrospective
Bone metastases [84] i. Control (N = 9) i. ↑ pain (VAS)
ii. Chemotherapy (N = 15) ii. 0–80% ↓ pain
iii. 2.5 g IV vitamin C (N = 15) during pain iii. 0–100% ↓ pain, mean 50% ↓ pain
Breast cancer [87] i. Control (N = 72) i. 15% pain
ii. 7.5 g IV vitamin C (N = 53) once weekly
for ≥ 4 weeks ii. 10% pain* (intensity of complaints during
adjuvant therapy)
Uncontrolled retrospective
Bone metastases [83] 2.5 g IV vitamin C (N = 11) once weekly for
3–10 weeks 0–100% ↓ pain (VAS), mean 49% ↓ pain
Case report
Breast cancer [133] 50 g IV vitamin C twice weekly for 4 weeks Before: 17% pain
After: 8% pain
(EORTC QLQ)
Terminal cancer [95] 30 g/day IV vitamin C for 1 week Before: 17% pain
After: 0% pain
(EORTC QLQ)
Metastatic breast cancer [81] 10 g/day oral vitamin C for 550 days Pain relief for >1 year
Breast cancer with skeletal metastases—severe
pain [81]5 g/day IV vitamin C for 7 days
8 g/day oral vitamin C for 70 days Complete ↓ bone pain from day 4
Bladder cancer with skeletal metastases—intense
pain [81]10 g/day IV vitamin C for 10 days
10 g/day oral vitamin C for 24 days Dramatic ↓ bone pain
Breast cancer with osteolytic metastases—severe
bone pain [81]10 g/day IV vitamin C for 7 days
10 g/day oral vitamin C for 27 days Complete ↓ bone pain
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Carr and McCall J Transl Med (2017) 15:77
provide dramatic improvements in pain relief in cancer
patients with bone metastases.
Over the last decade a number of studies have
attempted to quantify the effect of high dose vitamin C
on cancer-related symptoms such as pain (Table3). ese
studies have typically used the European Organisation
for the Research and Treatment of Cancer Quality of Life
Questionnaire (EORTC QLQ) [85]. e EORTC QLQ
assesses the typical cancer-related symptoms of pain,
fatigue, nausea/vomiting, dyspnea, appetite loss, sleep
disturbance, constipation, and diarrhea using a 4 point
Likert scale. A difference of 10–20% represents a medium
change in quality of life [86]. Most quality of life stud-
ies have reported decreases of>30% pain as assessed by
the EORTC pain scale in patients with cancer receiving
intravenous vitamin C (Table3). A retrospective study of
patients with breast cancer receiving 7.5 g intravenous
vitamin C once a week showed decreases in a number of
cancer-associated symptoms using a 3 point Likert scale,
including a 30% decrease in pain during adjuvant therapy
in the vitamin C group compared with the control group
[87].
Two prospective studies of patients with advanced
cancer who were administered intravenous vitamin C at
doses of 10–100g vitamin C (twice a week) have shown
30–44% decreases in pain using the EORTC pain scale
within 1–4weeks [88, 89]. Yeom etal. [88] recruited 39
patients with terminal cancer who subsequently received
10 g intravenous vitamin C twice weekly for 1 week,
followed by 4g/day oral vitamin C for 1week. Patients
exhibited 30% pain at baseline (as measured by the
EORTC-QLQ) and this decreased by one-third follow-
ing vitamin C infusion (P=0.013). Takahashi etal. [89]
recruited 60 patients with advanced cancer who received
25–100g intravenous vitamin C twice weekly for 4weeks.
Baseline pain in this cohort was 18% and this decreased
by 44% following vitamin C infusion (P<0.05, using the
EORTC-QLQ). A Phase I RCT designed to assess the
safety, tolerability and pharmacokinetics of high dose
intravenous vitamin C in patients with advanced cancer
also assessed quality of life as a secondary outcome [90].
is showed a decrease in pain for the few patients who
completed the EORTC-QLQ at 3 and 4weeks follow-up
(Table3).
Vitamin C andopioid analgesic requirements
e use of opioid analgesia is widely considered an
essential component in the management of moderate
to severe pain, however, opioid use is associated with a
well-documented side effect profile. Opioid effects, both
therapeutic and adverse, are dose dependent and subject
to significant inter-individual variability with bearing on
symptoms including nausea and vomiting, constipation,
and sedation and respiratory depression [91]. Co-analge-
sic agents and interventions that are opioid sparing may
improve the analgesic effect and reduce adverse effects.
Cancer-related pain is typically managed with opi-
oids [92]. In the early 1970s Cameron and Pauling [93]
described dramatic decreases in opiate dependence in
five patients with advanced cancer following high dose
vitamin C administration. ese patients were in consid-
erable pain due to skeletal metastases and were receiv-
ing large regular doses of opiate analgesics (morphine or
diamorphine). Within five toseven days of commencing
vitamin C, four of the five patients became completely
free from pain, and the fifth required only mild anal-
gesics [81]. Several of these cases are summarized in
Table 4. Interestingly, none of the patients experienced
any withdrawal symptoms despite having received opi-
ate analgesia for periods of weeks or months, nor did
they request that their opiate regime be continued. It is
interesting to note that vitamin C (at a dose of 300mg/kg
body weight/day for 4weeks) has been shown to dramat-
ically decrease the major withdrawal symptoms of heroin
addicts compared with a control group who were treated
with conventional medication only [94]. A complete
decrease in morphine requirement was also observed in
a patient with terminal cancer undergoing 30g/day vita-
min C infusion for palliative care [95]. Murata etal. [82]
reported a dose-dependent decrease in opioid require-
ment in patients with terminal cancer who received vita-
min C. In those who received 0.5–3g/day vitamin C, 50%
of the patients required opioid drugs, whereas only 17%
of those who received 5–30g/day vitamin C required opi-
oids, compared with 79% in the control group (Table4).
A recent study failed to confirm a decrease in opioid
requirement in 17 patients with a range of malignancies
[96], however, the study lasted for only 3days and the
vitamin C dose was lower than in studies that reported
positive findings (Table4).
ree recent placebo-controlled trials have been car-
ried out to investigate the effect of vitamin C on opioid
requirement for postoperative pain, two using intrave-
nous vitamin C [97, 98] and one using oral vitamin C [99].
In the most recent, 97 patients undergoing laparoscopic
colectomy for colon cancer were randomized to receive
intravenously 50mg vitamin C per kg body weight or
placebo infused immediately after induction of anaes-
thesia (Table4). A decrease in postoperative morphine
consumption was observed at 2h (P<0.05) in the vita-
min C group, as well as a decreased frequency of rescue
analgesia (P<0.01), and decreased pain at 2, 6 and 24h
post-surgery as assessed by the numeric pain rating scale
(P<0.05). In the other study, 40 patients undergoing uvu-
lopalatopharyngoplasty with tonsillectomy, which is nor-
mally associated with intense postoperative pain, were
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Page 8 of 14
Carr and McCall J Transl Med (2017) 15:77
randomized to receive intravenously either 3g vitamin C
or placebo 30min into the surgery (Table4). A decrease
in post-operative pethidine dose was recorded for the
vitamin C group compared with the placebo group (5 vs
46mg, P=0.0001), as well as a delay in the time of first
dose of pethidine use (12 vs 3h, P=0.003), and a decline
in the total number of times pethidine requested was
requested (0.2 vs 1.3 times, P=0.001). Visual analogue
scale scores were also lower in the vitamin C group at all
time points assessed (recovery, 6, 12, 24h, P= 0.001).
Opioid-based analgesics are typically used for postop-
erative analgesia, however these may complicate care by
causing excessive sedation and respiratory depression. In
contrast, no side effects were observed with the vitamin
C treatment.
In an earlier study, a single oral dose of 2g vitamin C
or placebo was given to 80 randomised cholecystectomy
patients 1h prior to anesthesia (Table4). Postoperative
morphine consumption and verbal numerical rating scale
scores for incisional pain were recorded for 24h. Mor-
phine consumption was lower in the vitamin C group
versus the placebo group (16 vs 23mg, P=0.02) and,
despite the lower opioid usage in the vitamin C group,
there was no difference in reported pain intensity or side
effects between the two groups [99]. Although baseline
plasma vitamin C concentrations were not determined,
blood samples were collected approximately 1 h post-
randomisation for vitamin C analysis. e placebo group
had marginal vitamin C status (23±17µmol/L) and the
vitamin C group had 57±28 µmol/L, although this is
possibly an underestimate as oral vitamin C uptake typi-
cally takes more than 1h to peak [100].
Support for the opioid-sparing effects of vitamin C
has come from murine studies. Co-administration of
1g/kg vitamin C with morphine prevented the develop-
ment of morphine tolerance and physical dependence
in mice [101]. Intraperitoneal administration of 400mg/
kg vitamin C significantly decreased self-administration
of morphine and withdrawal syndrome signs in rats
[102]. Vitamin C itself was shown to have antinocicep-
tive effects in mice (ED50 of 206mg/kg). Furthermore,
it exhibited not only additive effects, but also synergistic
effects, in combination with the opioids morphine and
tramadol [103]. us, vitamin C administration appears
Table 4 The eect ofvitamin C onopioid analgesic requirements
IV intravenous, NRS numeric rating scale, VAS visual analogue scale
*P<0.05
Study type Intervention Findings
Placebo controlled RCT
Laparoscopic colectomy—for colon cancer [97] i. Placebo (N = 48) i. 16 mg morphine at 2 h, frequency of rescue
analgesia: 1.4
ii. 50 mg IV vitamin C/kg body weight (N = 49)
prior to surgery ii. 14 mg morphine at 2 h*, frequency of rescue
analgesia: 0.8*, ↓ pain at 2, 6, 24 h (NRS)*
Uvulopalatopharyngoplasty with tonsillectomy
[98]i. Placebo (N = 20) i. 46 mg pethidine, first dose at 3 h, number of
requests: 1.3
ii. 3 g IV vitamin C (N = 20) 30 min into surgery ii. 6 mg pethidine*, first dose at 12 h*, number of
requests: 0.2*,
↓ pain at 6, 12, 24 h (VAS)*
Cholecystectomy [99] i. Placebo (N = 40) i. 23 mg morphine
ii. 2 g oral vitamin C (N = 40) prior to surgery ii. 16 mg morphine* (at 24 h follow up)
Uncontrolled prospective
Range of malignancies [96] 2 g oral vitamin C (N = 17) for 3 days Before: 360 mg/day opioids
After: 390 mg/day opioids
Controlled retrospective
Terminal cancer [82] i. Control (N = 19) i. 79% required narcotics
ii. 0.5–3 g/day oral vitamin C (N = 6) ii. 50% required narcotics
iii. 5–30 g/day oral vitamin C (N = 6) iii. 17% required narcotics
Case report
Intolerable fibrosarcoma-related pain [81] 10 g/day vitamin C for 19 days Better control of pain by opiates
Breast cancer with skeletal metastases—severe
pain [81]5 g/day IV vitamin C for 7 days No further need for opiates (from day 4)
8 g/day oral vitamin C for 70 days
Bladder cancer with skeletal metastases—
intense pain inadequately controlled by
morphine [81]
10 g/day IV vitamin C for 10 days No further need for opiates
10 g/day oral vitamin C for 24 days
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Page 9 of 14
Carr and McCall J Transl Med (2017) 15:77
to have potential application as an adjunctive therapy to
decrease opioid requirements and dependence.
Vitamin C andpain study design limitations
A major limitation of many of the vitamin C and pain
studies is inappropriate study design due to a general
lack of understanding around the pharmacokinetics of
vitamin C. Oral vitamin C is transported through the
intestinal epithelium via sodium-dependent vitamin C
transporters (SVCT-1) [104]. Levine and coworkers have
shown that oral vitamin C uptake becomes less efficient
as the dose increases due to saturation of the transport-
ers. Although an oral dose of 200mg vitamin C is com-
pletely absorbed, at doses of 500mg and 1250mg vitamin
C,<75% and<50% of the vitamin dose is absorbed [36].
Furthermore, steady state plasma vitamin C concentra-
tions rarely exceed 80µmol/L due to rapid renal clear-
ance. In contrast, intravenously administered vitamin
C, which bypasses the intestinally regulated uptake of
oral vitamin C, can provide plasma concentrations that
are 250 fold higher [36]. However, it should be noted
that because vitamin C has a short half-life in plasma of
approximately 2h [90], the high (millimolar) plasma con-
centrations provided by intravenous administration are
relatively transient. erefore, to maximise uptake and
plasma concentrations of vitamin C, the chosen intrave-
nous (or oral) dose should ideally be administered in sev-
eral smaller doses over the day [100].
Few of the cited pain studies have measured vita-
min C concentrations in their patients either before
or after administration of the vitamin C intervention.
Administration of vitamin C to patients who already
have adequate vitamin C status (i.e. ≥50 µmol/L) is
unlikely to have a significant effect and is a limitation of
many previous vitamin C studies [105]. Although many
patient cohorts are likely to have less than adequate vita-
min C status (i.e. <50µmol/L) and hypovitaminosis C
(<23µmol/L), baseline measures should still be collected
to allow stratification and/or sub-group analysis of the
patient cohorts. For example, we have shown that vol-
unteers with marginal vitamin C status (hypovitaminosis
C) have an attenuated response to recommended daily
intakes of vitamin C (i.e. 50mg/day), likely due to sub-
optimal tissue status, and as such need higher intakes to
reach adequate plasma concentrations [106]. is phe-
nomenon is likely to be even more pronounced in hos-
pitalized patients due to increased metabolic demands
for vitamin C due to surgery, trauma, infection or other
disease processes. Both surgical and infectious disease
patients have significantly lower than normal vitamin
C status and much higher vitamin C concentrations
(0.5–3 g/day) are required for restoration to normal
status [22, 23]. Similar trends are observed with patients
with cancer [37].
Although a number of placebo-controlled studies have
been carried out, primarily for CRPS, postherpetic neu-
ralgia and post-surgical pain, none of the cancer quality
of life studies have included placebo controls (Table3).
As such, it is not possible to determine the relative con-
tribution of the placebo effect in these studies, par-
ticularly as this effect tends to be more prevalent with
subjective measures such as pain [107]. Finally, a major
limitation of many vitamin C and pain studies is the lack
of mechanistic underpinnings.
Potential analgesic mechanisms ofvitamin C
As yet, there is no consensus as to the analgesic
mechanism(s) by which vitamin C could be acting. Oxi-
dative stress and inflammation have been implicated in
the sequelae of many pathologies, including arthritis,
CRPS, infection, cancer and surgical trauma. Vitamin C
is a potent antioxidant [108] which can scavenge a wide
range of reactive oxygen species and, thus, is capable of
protecting cells and tissues from oxidative damage [109].
Because of its well-known antioxidant properties, this is
the mechanism by which vitamin C is often assumed to
act in conditions where oxidative stress has been impli-
cated. is is, however, an overly simplistic assumption
due to the numerous enzymatic reactions in which vita-
min C acts as a cofactor in the body [9]. Vitamin C also
exhibitsanti-inflammatory properties, providing marked
decreases in markers of inflammation such as C-reac-
tive protein and pro-inflammatory cytokines, e.g. tumor
necrosis factor, interferon, and interleukins [110]. e
biochemical mechanisms underlying vitamin C’s ability
to decrease pro-inflammatory mediators are currently
unknown.
Vitamin C has a well-established role as a cofactor for
the synthesis of catecholamine neurotransmitters, and
hence is involved in neuromodulation [111]. Vitamin C
is a cofactor for the enzyme dopamine β-hydroxylase,
which converts dopamine into norepinephrine [112,
113]. Vitamin C may also facilitate the synthesis of dopa-
mine through recycling the cofactor tetrahydrobiopterin,
which is required for optimal activity of the rate-limiting
enzyme tyrosine hydroxylase [114]. A similar tetrahyd-
robiopterin recycling mechanism has been proposed for
vitamin C in the biosynthesis of the monoamine neuro-
transmitter serotonin [115]. It is noteworthy that both
serotonin and norepinephrine reuptake inhibitors show
efficacy in control of pain [116]. Ascorbate-deficient
animal models exhibit decreased norepinephrine con-
centrations compared with controls [117–119]. us,
administration of vitamin C to depleted patients may
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Page 10 of 14
Carr and McCall J Transl Med (2017) 15:77
enhance endogenous synthesis of these neurotrans-
mitters which may in turn contribute to the vitamin
C-dependent analgesia observed in some patients.
One currently unexplored analgesic mechanism
involves the potential role of vitamin C in the synthesis
of amidated opioid peptides. Vitamin C is a cofactor for
the enzyme peptidylglycine α-amidating mono-oxyge-
nase (PAM) [120]. PAM is the only known enzyme in
humans capable of amidating the carboxy-terminus of
peptide hormone precursors, a post-translational modi-
fication which is essential for their subsequent stability
and/or biological activities [121]. A number of amidated
neuropeptides have potent opioid activity. Endomor-
phin-1 and -2 are amidated tetrapeptides which have the
highest known selectivity and affinity for the µ-opioid
receptor of all known mammalian opioids [122]. Like
other opioid peptides, it is presumed that the endomor-
phins are generated via post-translational cleavage of a
larger precursor protein. For example, another amidated
opioid peptide with analgesic properties, which was first
identified in human adrenal medulla (adrenorphin or
metorphamide) [123, 124], is derived from the proteo-
lytic cleavage of proenkephalin A. A glycine-extended
precursor of the opioid peptide would then act as the
substrate for post-translational amidation by the ascor-
bate-dependent enzyme PAM to generate the active car-
boxy-amidated hormone (Fig.1).
e endomorphins are widely expressed in the central
nervous system and immune tissues [125]. ey have
well known analgesic properties, particularly for neu-
ropathic pain, but also have anti-inflammatory activity,
and have been proposed as potential therapeutic agents
in the treatment of chronic inflammatory diseases such
as rheumatoid arthritis and osteoarthritis [126]. As such,
it is tempting to speculate that some of the observed
anti-inflammatory effects of vitamin C could be due to
enhanced synthesis of endomorphins. It is noteworthy
that nervous and neuroendocrine tissues, where mono-
amine neurotransmitters and amidated neuropeptide
hormones are synthesised, contain the highest concen-
trations of vitamin C in the body [127]. Depletion of ami-
dated neuropeptide hormones has been demonstrated in
humans during severe infection [128], which is known to
significantly deplete vitamin C concentrations [23], and
administration of vitamin C to animal models enhances
the synthesis of these PAM-derived hormones [129].
erefore, it is possible that depletion of vitamin C dur-
ing acute or chronic disease or trauma could contrib-
ute to pain symptoms due to sub-optimal biosynthesis
of analgesic neurotransmitters and neuropeptide hor-
mones. e observation that vitamin C administration
significantly decreases the requirement for opioid analge-
sics (Table4) lends support to this hypothesis.
Calcitonin has been used for decades as a treatment
for osteoporosis and other diseases involving acceler-
ated bone turnover [130]. Calcitonin also has a direct
analgesic effect on bone pain and has been utilised for
improving the pain of acute vertebral fractures, malig-
nant bone metastases, Paget’s disease, and complex
regional pain syndrome [130]. It is interesting to note
that calcitonin is an amidated peptide hormone, requir-
ing post-translational amidation by PAM for full activity
of the mature hormone [131]. us, vitamin C is likely
to be also required as a cofactor for the synthesis of cal-
citonin. e analgesic properties of calcitonin appear
Fig. 1 Proposed synthesis of endomorphin-1 by the vitamin
C-dependent enzyme peptidylglycine α-amidating monooxygenase
(PAM). The enzyme comprises a peptidylglycine α-hydroxylating
monooxygenase (PHM) domain, which converts glycine-extended
peptides into a hydroxyglycine intermediate, and a peptidyl
α-hydroxyglycine α-amidating lyase (PAL) domain, which converts the
hydroxyglycine intermediate into an amidated product. AA ascorbic
acid, DHA dehydroascorbic acid
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Page 11 of 14
Carr and McCall J Transl Med (2017) 15:77
to be independent of its effects on bone resorption and
are possibly mediated through enhanced release of the
potent analgesic β-endorphin [130]. erefore, vitamin
C may exhibit analgesia both indirectly, through calci-
tonin-dependent modulation of endorphins, and directly
through enhanced synthesis of endomorphins.
Conclusions
Acute and chronic pain can be debilitating for patients,
particularly if not adequately managed by conventional
analgesics. Accumulating evidence indicates that vita-
min C can exhibit analgesic properties in some clini-
cal conditions, thus potentially mitigating suffering and
improving patient quality of life. Pain is costly because
it requires medical treatment, complicates treatment of
other conditions and results in lost productivity. In the
USA the annual cost of pain was greater than the annual
costs of heart disease, cancer, and diabetes [132]. Vita-
min C is cost effective and appears to be a safe and effec-
tive adjunctive therapy for specific pain relief. Notably, it
decreases the requirement for opioid analgesics, particu-
larly post surgically and for bone metastasis, thus poten-
tially diminishing the deleterious side effects of opioids.
Future high quality studies are required to confirm these
findings. Inclusion of placebo controls is preferred due
to the subjective nature of pain, however, this can some-
times be difficult to justify in certain patient groups,
hence the paucity of placebo-controlled trials for intrave-
nous vitamin C and cancer quality of life. Ideally, studies
should also include patients who have less than adequate
vitamin C status at baseline (i.e.<50 µmol/L) to ensure
that their concentrations are able to increase following
supplementation. Overall, future studies should endeavor
to ascertain the following aspects: measurement of vita-
min C concentrations at baseline and following inter-
vention to determine if specific patient groups respond,
determination of the optimal rout of administration (i.e.
enteral or parenteral), the optimal dose and frequency of
vitamin C administration (which will likely differ depend-
ing upon the type of pain and associated conditions), and
the potential mechanisms of action of vitamin C.
Abbreviations
AA: ascorbic acid; CRPS: chronic regional pain syndrome; DHA: dehydroascor-
bic acid; EORTC: European Organisation for the Research and Treatment of
Cancer; IV: intravenous; NAS: numerical analogue scale; NRS: numeric rating
scale; PAL: peptidyl α-hydroxyglycine α-amidating lyase domain; PAM: pepti-
dylglycine α-amidating mono-oxygenase; PCIG: patient global impression of
change; PHM: peptidylglycine α-hydroxylating monooxygenase domain; PHN:
postherpetic neuralgia; QLQ: quality of life questionnaire; RCT: randomized
controlled trial; VAS: visual analog scale.
Authors’ contributions
AC conceived the novel vitamin C-dependent opioid synthesis mechanism
and the review topic, and wrote the vitamin C-related sections; CM wrote
the general pain-related sections. Both authors read and approved the final
manuscript.
Authors’ information
AC is a biomedical researcher with many years’ experience running human
intervention studies investigating the bioavailability and health effects of
vitamin C. CM is a clinician with many years’ experience working to improve
the experience of patients with pain.
Author details
1 Department of Pathology, University of Otago, Christchurch, PO Box 4345,
Christchurch 8140, New Zealand. 2 Centre for Postgraduate Nursing Studies,
University of Otago, Christchurch, PO Box 4345, Christchurch 8140, New
Zealand.
Acknowledgements
We thank Professors Harri Hemilä and Marie Crowe for critically reviewing the
manuscript and providing helpful suggestions. A.C. is the recipient of a Sir
Charles Hercus Health Research Fellowship from the Health Research Council
of New Zealand.
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials
Data sharing not applicable to this review as no datasets were generated or
analysed for the review.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Received: 27 January 2017 Accepted: 5 April 2017
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