FormalPara Key Summary Points

Despite extensive research efforts, the prevalence of chronic pain continues to increase, indicating a need for closer investigation into potential treatment gaps.

Analgesics, although effective in modulating pain, do not target the root cause of pain, often originating from tissue damage induced by oxidative stress.

This review examines the therapeutic efficacy of antioxidant therapy using vitamin C as a prime example due to its potent antioxidant properties and involvement in the synthesis of pain-related neurotransmitters.

Vitamin C has been studied predominantly in peri- and post-operative scenarios, infections, and tumor-induced pain, where it was often administered via injection or infusion for enhanced bioavailability.

Meta-analyses and randomized controlled trials indicate the potential of antioxidant therapy with vitamin C in reducing the risk of complex regional pain syndrome (CRPS), post-herpetic neuralgia, mitigating postoperative pain, and decreasing opioid consumption, advocating for expanded clinical trial investigations.

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Introduction

Pain is a significant humanitarian and fundamental medical issue and is the most common reason for seeking medical treatment. Despite extensive international multidisciplinary research aimed at improving patient care, the prevalence of impairments caused by pain conditions is on the rise worldwide [1,2,3]. This situation highlights the existence of a drug therapy gap that needs to be addressed. According to the definition provided by the International Association for the Study of Pain (IASP), pain is described as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [4].

A considerable cause of tissue damage is oxidative stress. It occurs when more reactive oxygen species (ROS) are formed than can be neutralized by low molecular or enzymatic antioxidants. Oxidative stress is involved in the pathophysiology of many diseases or conditions that are associated with pain. In surgical interventions, ROS are mainly formed during reperfusion [5]. In inflammation, ROS are produced by immune cells to eliminate pathogens extracellularly and to induce redox-sensitive pro-inflammatory signaling pathways intracellularly. In the absence of sufficient antioxidant capacity to scavenge excess ROS, healthy tissue is damaged and renewed inflammation with chronification may result [6]. This applies to both infections and chronic inflammatory diseases such as arthritis. In tumor tissue, oxidative stress is caused by chronic subacute inflammation and, to a greater extent, by chemotherapy and radiation [7, 8]. In wound-healing disorders, persistent inflammation and oxidative stress also play an important pathophysiological role [9]. Oxidative stress is also a key factor in painful conditions like fibromyalgia, where inflammation and tissue injury are not obvious [10,11,12]. The result is a strong consumption of antioxidants such as ascorbate. In addition, there is increasing evidence of a direct link between oxidative stress and pain, and consequently, pain relief through the administration of antioxidants [13].

As described above, oxidative stress plays a pathophysiological role in many diseases associated with pain. As oxidative stress leads to tissue damage, combating it with antioxidants such as l-ascorbate could be an effective therapeutic approach. l-ascorbate is the biologically active form of vitamin C in blood and tissue. Unlike ascorbic acid, it can no longer release acidic valence under physiological conditions. The administration of high-dose l-ascorbate does not interfere with the sensitive acid–base balance in human tissues. Therefore, for high-dose infusion therapy, l-ascorbate should be used. It should definitely be the ingredient of approved remedies for high-dose therapy (> 1 g). l-ascorbate as well as ascorbic acid products both need to be declared as ascorbic acid due to drug and therapeutic device regulations.

Pharmacological pain therapy, which includes non-steroidal anti-inflammatory drugs, steroidal analgesics, opioids, and supra-additive substance classes such as antidepressants and anticonvulsants, should modulate pain. Ascorbate deficiency due to excessive generation of reactive oxygen species (ROS) during inflammation, injuries, surgical procedures, and oncologic diseases leads to l-ascorbate consumption resulting in oxidative stress.

Basic research on pain perception motivates us to assume that oxidative stress is a key factor in acute and chronic pain and thus could be addressed by antioxidative therapy such as l-ascorbate [13,14,15,16,17]. Even suboptimal ascorbate plasma levels are being associated with an increased prevalence of dysfunction and back pain [18] and an increased need for analgesics postoperatively [19].

Ascorbate is one of the most effective physiological antioxidants [20] and supports the recycling, formation, and activity of other antioxidants [21]. Additionally, it has important anti-inflammatory effects, such as reduction of IL-1, IL-6, TNF, CRP, histamine levels, and increase of IL-10, IL-4, and Nrf2 levels [22].

By treating ascorbate deficiency and therefore reducing oxidative stress, l-ascorbate may reduce tissue damage and is an option for effective pain prevention and treatment [23]. There is a substantial evidence base on the use of l-ascorbate or ascorbic acid for pain of various etiologies. l-ascorbate serves as a co-factor in the formation of neurotransmitters such as serotonin, dopamine, norepinephrine, opioid peptides, and calcitonin, which are essential for pain modulation and relief [23]. It is also crucial for collagen synthesis, thereby contributing to the stability of the entire musculoskeletal system. Musculoskeletal pain often goes along with ascorbate deficiency. As a co-factor for TET enzymes, l-ascorbate plays a significant role at the epigenetic level in bone substance and wound healing, particularly neuronal healing [24,25,26].

The aim of this project was to evaluate the available literature on l-ascorbate and ascorbic acid with a clinical focus on pain therapy via a critical assessment. There is still minor disagreement about the usefulness of vitamin C in the available literature. Many contributions do not distinguish between different forms of vitamin C, and thus are inconclusive with respect to l-ascorbate. Due to substantial differences in the genesis, etiology, and pathophysiology of pain, research studies are naturally heterogeneous and thus cannot be consolidated under one umbrella. This contradicts a systematic review as preparatory step for a statistical meta-analysis. The few published meta-analyses aiming at clinical evidence are not fully conclusive with respect to ascorbate pain relief. Primary reasons for this are the limited number of available controlled clinical trials in the various medical specializations and rather small patient numbers.

The strategy was to analyze original clinical study articles as well as systematic review articles by means of critical assessment. Apart from the usual quality criteria of clinical research papers, there was also a focus on the appropriateness of the applied study formats and statistical methods (see Table 2). Hence, the results of this project go beyond evidence levels, also pointing to technical weaknesses when present (entries in Table 2 under the header “methodological quality of research”). This allows the interested reader to gain a deeper insight into the obtained degree of evidence from the analyzed research publications. The goal was to find sufficient literature evidence to derive recommendations for pain therapy with l-ascorbate.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Therefore, an ethics committee approval was not required for this review.

Methods

As a direct consequence of the above given arguments concerning the immanent heterogeneity of clinical vitamin C studies, it was decided to perform a critical assessment of the available literature. For each condition of pain, for which sufficient literature could be identified, evidence levels were specified. A literature search was conducted in PubMed with the mesh terms “pain” and “ascorbic acid” and the further filters for clinical studies (Clinical Study, Clinical Trial, Comparative Study, Controlled Clinical Trial, Evaluation Study, Meta-Analysis, Multicenter Study, Observational Study, Pragmatic Clinical Trial, Randomized Controlled Trial) for the time period 1980 to 2023. The obtained material was complemented by articles retrieved from secondary literature. Two experts identified independently of each other relevant articles describing clinical trials and meta-analyses. All articles underwent a critical assessment in the light of evidence-based medicine. The purpose of this work was to establish specific pain therapy guidance for intravenous l-ascorbate. The evidence levels were assigned to the articles following the recommendations in the article of Burns PB et al. ([52]; see therein Table 4) for evidence-based medicine. In addition to the levels of evidence, the methodological quality of each article was reviewed. Criteria were (1) an adequate characterization of the study design, (2) correctness of the applied statistical inference methods, (3) sufficient number of patients, and (4) quality of representation of results. The methodological review is summarized for each article in high, adequate, or low quality. The evidence levels and the methodological review results are displayed in Table 2. An ethics committee approval was not required for this critical assessment of the literature.

Results

The search revealed 80 results. Then various articles had to be excluded from further analysis. The reasons for the exclusion of articles are listed in Table 1. The material obtained comprised 14 research papers suitable for critical assessment (see Table 2). Ten additional publications could be identified via secondary literature. Finally, the 24 selected articles underwent a critical assessment in the light of evidence-based medicine plus methodological correctness. However, even among those selected 24 articles, the research quality differs a lot. Six studies are of high quality [28, 34, 39, 42,43,44], 13 studies are of adequate quality [29,30,31, 33, 35,36,37, 40, 41, 45, 47,48,49], and five of low quality [32, 38, 46, 50, 51].

Table 1 Reasons for the exclusion of studies (f gives the frequency of occurrences)
Full size table
Table 2 List of clinical studies and meta-analyses that have investigated the effects of ascorbate/ascorbic acid on disorders associated with pain
Full size table

The obtained 24 studies can be subdivided into six disease groups, which are described underneath and characterized by their levels of evidence. The overall quality of the reviewed publications is sufficient to draw conclusions about vitamin C treatment schemes within these specific indications.

Prevention of Complex Regional Pain Syndrome (CRPS)

After trauma and surgery to the wrist and ankle, ascorbate/ascorbic acid (≥ 500 mg/day oral for at least 6 weeks) reduces significantly the risk of CRPS.

Evidence level 1a due to several meta-analyses [29, 30].

There is one prospective, double-blinded, randomized placebo-controlled trial (n = 68, evidence level 1b) so far that has investigated the effects of parenteral ascorbate [31]. Although both groups received ascorbate/ascorbic acid orally for 6 weeks, local injection of 500 mg ascorbate (adjuvant in Bier block) significantly reduced the incidence of CRPS 12 weeks after surgery (22.9 vs. 45.5%, p = 0.04). Via logistic regression analysis it was shown that the only significant contribution in predicting the incidence of CRPS has come from the intervention variable (OR 0.26, CI95% 0.08–0.85; p = 0.027).

Prevention of Post-Herpetic Neuralgia (PZN)

In acute herpes zoster infection, ascorbate/ascorbic acid intravenously reduces the risk of PZN.

Evidence level Ib for the dosage of 5 g ascorbic acid three times in 1 week (RCT, n = 87) [32];

Evidence level IV for the dosage of 7.5–15 g l-ascorbate two to three times a week for 2 weeks (NIS, n = 67) [33].

Reduction in Post-Operative Pain

Peri- or postoperatively, parenteral ascorbate/ascorbic acid reduces significantly post-operative pain and the need for analgesics (opioids, etc.).

Evidence level Ia; two meta-analyses of various dosages (1–3 g) administered parenteral [28, 34].

Pain Reduction in Neuralgia

l-ascorbate might help to reduce acute pain and the incidence of post-herpetic neuralgia.

In a double-blinded placebo-controlled trial, parenteral l-ascorbate in a dosage of 2.5 g administered three times within 1 week could significantly reduce spontaneous post-herpetic neuralgia [36].

In a multicenter prospective cohort study, parenteral administered l-ascorbate in a dose of 7.5–15 g two to three times a week for a period of 2 weeks (on average 8 infusions) reduced acute pain significantly within these 2 weeks [33]. However, in a randomized controlled trial, no significant pain reduction was observed within the first 6 weeks but the incidence of post-herpetic neuralgia was significantly reduced [32]. In the latter study, a lower ascorbic acid dose and a shorter treatment duration were applied (5 g three times within a week). This might be the reason for inconclusive pain reduction results.

Evidence level Ib for post-herpetic neuralgia (RCT n = 41) [36];

Evidence level III for positive effects on acute herpetic neuralgia (NIS; n = 67) [33]

Evidence level Ib for no effects on acute herpetic neuralgia (RCT; n = 87) [32].

Reduction in Inflammation-Related Pain

Oral ascorbate/ascorbic acid (1 g daily for several weeks) significantly reduces pelvic pain with a history of endometriosis and/or infertility (in combination with vitamin E) according to a randomized trial (p = 0.005).

Evidence level Ib for endometriosis (RCT n = 59) [37]

Oral ascorbate/ascorbic acid (1 g daily for several weeks) reduced pain in osteoarthritis of the hip joints and/or the knee joints in a multicenter randomized cross-over trial (p = 0.008).

Evidence level Ib for osteoarthritis (RCT n = 133) [38]

Reduction in Tumor-Related Pain

Parenteral l-ascorbate (≥ 20 g per day) application reduced pain significantly in quality-of-life studies of advanced cancer patients (p < 0.01).

Evidence level Ib for l-ascorbate in combination with hyperthermia (RCT n = 97) [39].

Evidence level III for ascorbate/ascorbic acid (prospective observational pre-post study, n = 60) [40]

Evidence level III for ascorbate/ascorbic acid (prospective observational pre-post study, n = 39) [41]

Parenteral Versus Oral Application

Elevated blood levels of ascorbate, which necessitate parenteral (intravenous) administration of l -ascorbate, can more quickly and efficiently address tissue deficiency compared to oral intake [27]. This finds support in a meta-analysis for the setting of surgery: only parenteral administration, not oral administration, is associated with pain reduction and a decreased need for analgesics [28]. For other pain conditions, oral administration is shown to be effective [29, 30].

Discussion

ROS are generated by immune cells during inflammation, produced during surgical interventions involving reperfusion, and induced by chemotherapy and radiotherapy. The vulnerability of the vascular endothelium and nervous tissue to oxidative stress is particularly important in terms of pathophysiology [6]. Therefore, l-ascorbate could be an approach to causal therapy and pain relief. Many diseases that are accompanied by pain are associated with an ascorbate deficiency. Therefore, l-ascorbate could represent a safe and effective adjuvant therapy option for pain prophylaxis and the treatment of orthopedic-, tumor-, and infection-related pain. It could have the potential to alleviate pain and to reduce the need for opioid analgesics without causing withdrawal symptoms. The analgesic effect of l-ascorbate can be attributed to its tissue- and nerve-protective properties, including its anti-oxidative and anti-inflammatory effects. Furthermore, as an enzymatic co-factor, it plays a vital role in the formation of neurotransmitters crucial for pain modulation.

Prevention of Complex Regional Pain Syndrome (CRPS)

The efficacy of oral l-ascorbate/ascorbic acid for several months has been shown by its ability to reduce the risk of CRPS after trauma or surgery. In article [31], it is demonstrated that in situ loading of ascorbate has an additional positive effect. This suggests that higher tissue levels of ascorbate during surgery may further reduce the risk of CRPS.

Against the background of the assessed articles (meta-analyses and RCTs), we suggest parenteral high-dosage use as long as the inflammation and oxidative burst at tissue level persists. Oral application of ascorbate can enhance outcome at days without parenteral therapy to provide continuous serum levels above usual intake during acute pain conditions. The benefit of perioperative parenteral ascorbate should be further investigated.

Prevention of Post-Herpetic Neuralgia (PZN)

Parenteral l-ascorbate administration for prevention of PZN following an acute herpes zoster infection can reduce the requirement for analgesics. During acute herpes zoster disease, the oxidative burst releases ROS, which damage the surrounding nerve tissue in particular. The RCT [32] on acute herpes zoster infection observed significantly fewer PZN in the vitamin C group in which patients received three infusions at the beginning of the disease. In the observational study [33], in which the course of the disease was monitored after 2 weeks of vitamin C infusion therapy, the low risk of PZN, which was only 6.4%, was particularly striking. These results support the hypothesis that anti-oxidative therapy during acute infection protects nerve tissue and can thus prevent pain. Parenteral application with discontinuous ascorbate serum levels could possibly be inferior in outcome compared to when parenteral and oral administration with formulas with high oral bioavailability are combined. Overall, parenteral administration of l-ascorbate emerges as a promising approach for pain management and prevention, offering a complementary therapeutic option alongside conventional treatments that should be further investigated.

Reduction in Post-Operative Pain

In almost all RCTs considered in the two systematic reviews, a single perioperative bolus of ascorbate/ascorbic acid was used. This could not shed light on the possible additional benefits from repeated administrations for maintaining a high circulating level. Moreover, the follow-up periods of the included trials were too short (i.e., 24–48 h) to elucidate the long-term antinociceptive benefit of ascorbate/ascorbic acid. Previous studies have demonstrated a reduction in risk for chronic pain (CRPS) after post-operative long-term administration.

One of the RCTs determined ascorbate plasma levels [35]. Although ascorbate plasma levels at the end of surgery were significantly higher in the ascorbate group than in the placebo group, they were still in the range of hypovitaminosis. The patients who received 50 mg/kg body weight parenteral ascorbate at the start of surgery were apparently able to maintain higher plasma ascorbate concentrations throughout the surgery and in the early postoperative period. The decreased morphine consumption during the first 2 h after surgery and the decreased pain scores at rest during the first 24 h may have been associated with this. While the single infusion of high-dose ascorbate might have inhibited generation of ROS during surgery and contributed to reduced morphine consumption during the immediate postoperative period, the short half-life of the ascorbate does not support a sustained elevation of the plasma ascorbate concentration. This could explain why there were no differences between groups in morphine consumption by 6 and 24 h postoperatively after elective laparoscopic colectomy under general anesthesia. It suggests that a higher dose with a prolonged application time may be useful to maintain sufficient ascorbate concentrations and support analgesic effects [35]. To avoid hypovitaminosis during surgical interventions required through enhanced consumption, we recommend applying 100–200 mg/kg body weight of l-ascorbate. To address an additional therapeutic effect on wound healing or pain prevention and therapy it is safe to dose even higher 0.2–0.5 g/kg body weight. Ideal therapeutic dosage has to be investigated further.

Reduction in Infection-Related Pain

In this context, the effects of intravenous vitamin C on herpes zoster were specifically investigated. However, the study's current state is insufficient for a conclusive evaluation. In the observational study, over one-third of the patients received only vitamin C without analgesics or antivirals, resulting in a notable reduction in pain by an average of 3.7 points on the VAS scale after just 2 weeks [33]. The randomized controlled trial (RCT) design hampers a definitive assessment of vitamin C's influence, as all patients received extensive pain medication during the acute phase. All patients were intravenously injected with 5 mg/kg of acyclovir for 5 days and orally treated with 100 mg of gabapentin and analgesics (acetaminophen 250 mg/ibuprofen 200 mg/codeine phosphate 10 mg mixture) three times a day to control pain. This may explain why significant differences in pain intensity only emerged after 8 weeks [32].

Reduction in Inflammation-Related Pain

Studies on chronic inflammatory pain have so far been limited to oral administration, which, as described above, is mostly associated with significantly lower bioavailability. Due to the severity of the inflammatory condition, we recommend an additional parenteral administration during continuous oral ascorbate therapy to enhance outcome. The effects of antioxidant infusion therapy in inflammation-related pain should be further investigated in clinical studies.

Reduction in Tumor-Related Pain

The study situation in oncological patients and pain is too weak for a conclusive assessment (observational studies and one RCT with two therapeutic interventions, hyperthermia and vitamin C, in the verum group). However, the available observational studies show a significant reduction in pain in patient groups with advanced disease where pain reduction for other reasons is unlikely. The effects of intravenous high-dose vitamin C should be further investigated in RCTs.

In advanced disease cancer patients, the consumption of ascorbate is generally massive and underestimated. Therefore, this fact should be taken into consideration when planning the required dosages and frequency of treatment. Dosages higher than 0.5 g/kg body weight l-ascorbate could produce oxidative stress to tumor cells at peak serum levels, which could bring about an additional cancer-specific therapeutic benefit.

Conclusions

The current research indicates that l -ascorbate is an effective, safe, and economically favorable integrative treatment option for various pain conditions. As some results are inconsistent, those studies of high scientific quality support the efficacy of the treatment with l-ascorbate, addressing the root cause of tissue damage and inflammatory mediator burst. Despite this fact, the integrative treatment is still discussed controversially and hence underestimated in preventive and treatment protocols. The authors suggest taking l-ascorbate into consideration for prevention and treatment of acute and chronic pain. Oral ascorbic acid administration usually does not provide sufficient bioavailability to meet the needs of addressing major inflammatory conditions. Parenteral (intravenous and tissue) administration is more effective and can be supported by l-ascorbate formulas with a high bioavailability on days without parenteral treatment options. The right dosage of l-ascorbate should be selected according to clinical severity of pain and oxidative inflammatory mediator activity. Studies have shown that a dosage between 0.1 and 1 g/kg body weight is safe while observing only few contraindications. The authors suggest using the range of 0.2–0.5 g/kg body weight as effective, thus providing an intense antioxidative activity. Cancer-related pain can be treated with higher doses up to 1 g/kg body weight to achieve an additional effect on cancer cells while acting oxidative at peak serum levels.

Overall, there is a high demand for further research into various pain conditions that have not yet been investigated. In general, there is a lack of studies comprising a sufficient number of patients allowing to perform meta-analyses for the sake of clinically convincing results. In terms of optimal frequency and dosage as well as intermittent or continuous administration, dosage-finding studies have to be done separately for each pain condition to allow mandatory recommendations or to provide reliable treatment protocols.