Herbal Medicine for Pain Management: Efficacy and Drug Interactions

Complementary and alternative medicines such as herbal medicines are not currently part of the conventional medical system. As the popularity of and global market for herbal medicine grows among all age groups, with supporting scientific data and clinical trials, specific alternative treatments such as herbal medicine can be reclassified as a practice of conventional medicine. One of the most common conditions for which adults use herbal medicine is pain. However, herbal medicines carry safety concerns and may impact the efficacy of conventional therapies. Unfortunately, mechanisms of action are poorly understood, and their use is unregulated and often underreported to medical professionals. This review aims to compile common and available herbal medicines which can be used as an alternative to or in combination with conventional pain management approaches. Efficacy and safety are assessed through clinical studies on pain relief. Ensuing herb–drug interactions such as cytochrome modulation, additive and synergistic effects, and contraindications are discussed. While self-management has been recognized as part of the overall treatment strategy for patients suffering from chronic pain, it is important for practitioners to be able to also optimize and integrate herbal medicine and, if warranted, other complementary and alternative medicines into their care.


Introduction
Complementary and alternative medicine (CAM) incorporates a wide range of practices, interventions, therapies, applications, professions, theories, and claims that are not currently part of the conventional medical system. Over time and with supporting scientific data and clinical trials, a specific CAM treatment such as herbal medicine can be reclassified as a practice of conventional medicine. With the present positive social perspective on herbal medicine, its popularity is growing among all age groups [1]. It is a common belief that CAM enables individuals to be more involved with their care, control or offset the adverse events of conventional medicine, and/or find harmony with their culture or philosophies [2]. Patients often seek every possible option for receiving the benefits of medical care while avoiding adverse events [3].
One of the most common conditions in the United States for which adults use CAM is pain. This includes musculoskeletal pain such as cervical, lumbar, or joint pain as well as specific conditions such as arthritis or migraine. Although pain is a physiological and vital response to potential or actual tissue injury, in some cases (such as musculoskeletal pain or special conditions like arthritis) it can become chronic and cause biological changes to the central nervous system or peripheral tissues. Chronic pain can be debilitating and constitutes a high social and economic burden on the health system [4]. In some cases, due to adverse drug reactions, lack of efficacy, or high risk for serious complications, traditional treatments such as opioids or non-steroidal anti-inflammatory drugs (NSAIDs) must be Among the herbs reviewed, SJW has the most potential for drug interaction. Adverse events are mostly due to its drug interaction with other selective serotonin reuptake inhibitors (SSRIs, such as paroxetine), MAOIs, opiates, tricyclic antidepressants, cold and flu medications which can lead to serotonin syndrome [14,15]. It has also been shown to be uterotonic in in vitro studies and rarely causes photosensitivity [10]. Its flavonoid components especially quercetin have been shown to have analgesic activity [16]. SJW has also been found to cause nausea, vomiting and anxiety when taken with sertraline, an antidepressant used in the treatment of chronic pain [17].
Hyperforin activates a regulator of the cytochrome P450 (CYP450) 3A4 transcription and results in the expression of 3A4 in the hepatocytes. St. John's wort can also induce 2C9, 2D6, 2C19, 2E1, and 1A2. Concomitant use of opioids such as fentanyl, hydrocodone, codeine, tramadol, oxycodone and methadone with SJW may decrease the opioid concentrations and lead to withdrawal symptoms. Conversely, discontinuing the SJW may also cause increased opiate concentration causing toxicity [18][19][20][21]. The likely mechanism of this interaction between SJW and codeine is by inducing CYP3A4 metabolism, codeine conversion to the inactive norcodeine increases, resulting in less codeine being available for CYP2D6 to form its active metabolite morphine. It has also been reported that SJW active agents can inhibit MAOI A and B, but at concentrations up to 10 µM it may not be clinically relevant [22]. SJW's analgesic effect plus its interaction with other analgesics such as fentanyl, morphine, ketamine, oxycodone has been studied in clinical trials.
Clinical studies and relevant review article are summarized in Table 1. SJW does not alter fentanyl pharmacodynamics or clinical effects, likely does not affect hepatic clearance or blood-brain barrier efflux. Taking SJW will likely not respond differently to intravenous fentanyl for analgesia or anesthesia [23].

Journal of Pharmacological
Sciences 2014 Clinical trial with one-way analysis of variance (ANOVA) for repeated measures 8 human volunteers, 170 rodents, 5 days treatment, up to 1 h follow up Rodents (adult male Swiss albino mice and rats), healthy male volunteers receiving oral morphine co-administered with SJW 300 mg tablets or morphine alone A low dose of SJW significantly potentiated oral 10 mg morphine's analgesic effect in humans and rodents [24]. Oral SJW 300 mg versus placebo, six women and six men SJW decreased the exposure to oral S-ketamine but was not associated with significant changes in the analgesic or behavioral effects of ketamine. Usual doses of S-ketamine if used concomitantly with SJW may become ineffective [25]. Clewell Oral SJW (2700 µg total hypericin daily, n = 27)) versus placebo tablet (n = 27), up to 6 paracetamol 500 mg tablets could be used daily as escape medication There was a trend of lower total pain score with oral SJW compared to the placebo group. However, none of the volunteers' pain ratings were significantly changed by SJW as compared to placebo. Complete, good, or moderate pain relief was reported by nine patients taking SJW and two with placebo. In conclusion, SJW does not have a significant effect on pain due to polyneuropathy [27].

Review Article
Galeotti, N. Journal of Ethnopharmacology 2017 Review Article -Preclinical animal, in vivo and in vitro studies, clinical trials with dental pain Preclinical animal studies showed the potential of low doses SJW dry extracts to induce antinociception, mitigate acute and chronic hyperalgesic states, and to augment opioid analgesia.
Clinical studies showed SJW is promising in dental pain conditions. SJW analgesia appears at low doses (5-100 mg/kg), decreasing the risk of herbal-drug interactions caused by hyperforin, a potent CYP enzymes inducer [28].

Ginger
Ginger, also known as Zingiber officinale, has beautiful flowers but its tuberous rhizome has been used as a spice and medicine by herbalists mostly in India and China for the past 2500 years. The plant is found in most tropical countries [29,30]. It has uses for muscle pain and swelling, arthritis, headaches, digestive and appetite problems, prevention of motion sickness, postoperative nausea and vomiting, hyperemesis gravidarum, and also cold and bacterial infections due to its anti-oxidant mechanism [11,31]. Gingerols, especially 6-gingerol (Figure 2), are the active components of ginger. Ginger's anti-emetic activity is not well understood but it is proposed to be caused by direct stimulation of the gastrointestinal tract or by antagonizing serotonin in the gut or central nervous system [32][33][34]. Its anti-inflammatory effects come from inhibiting arachidonic acid metabolism [33,34]. Based on the available data there is a delayed therapeutic action and therefore it does not help treat acute pain conditions such as exercise-induced muscle pain [35][36][37][38]. The adverse effects of ginger include drowsiness, excessive sedation, and arrhythmia [11], and perioperative physicians should be aware of its potent thromboxane-synthetase inhibition, which interferes with platelet aggregation and increases bleeding time based on in-vitro studies [40][41][42]. However, it has not been proven in in vivo human studies [43]. The concomitant use of ginger with other herbs or drugs with similar pharmacologic potential such as naproxen may increase the risk of bleeding and therapy modification should be considered [22]. If needed platelet functions status testing should be done before neuraxial or regional anesthetic procedures in any patient with bleeding or bruising history.
An animal study into ginger-drug interactions have found that combining acetaminophen with dried powdered ginger rhizome significantly enhanced acetaminophen's anti-nociceptive effect and improved cognitive disturbances associated with chronic pain [44]. Another study noted that ginger root extract injected in rats before a sub-effective dose of morphine elicited a significant anti-nociceptive effect, higher than in groups treated with either morphine or the extract alone [45].
Clinical studies and relevant review articles are summarized in Table 2. (Table 2

Turmeric
The rhizome of the turmeric plant also known as Curcuma longa contains an active polyphenolic compound called curcumin ( Figure 3). It has traditionally been used as an antiseptic, anti-inflammatory agent for wound healing as well as an antioxidant and analgesic agent [54,55]. Curcumin can regulate inflammatory cytokines such as interleukin (IL)-1 beta, IL-6, IL-12, Tumor necrosis factor (TNF)-alpha, interferon (IFN) gamma, and associated AP-1, NF-kappa B, and JAK-STAT signaling pathways. With its anti-inflammatory effects, it has been used in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis [56]. In terms of drug interactions, turmeric supplementation of paclitaxel chemotherapy was found to improve the quality of life and pain scores in breast cancer patients [57]. Oral turmeric is well tolerated and safe for general use. Due to its poor bioavailability, higher doses are often used to achieve a systemic effect [59]. Studies have shown curcumin can inhibit platelet-activating factor and arachidonic acid platelet aggregation [60]. Due to its anti-thrombotic effects, concomitant use of turmeric with other drugs with similar pharmacologic potential such as naproxen may increase the risk of bleeding, and therapy modification is recommended.
Several pre-clinical studies have investigated interactions between curcumin and drugs. One such study in mouse models of acute nociceptive pain demonstrated a synergistic interaction in combination with pregabalin [61]. Curcumin was found to downregulate opioid-related nociceptin receptor 1 gene expression, which codes for nociceptin opioid peptide receptor (NOP), one of the four opioid receptors. This suggests an inhibitory effect on morphine-induced activation of the same gene, possibly decreasing tolerance and addiction to morphine and other analgesic opioids [62]. A synergistic anti-nociceptive effect was also noted in the combination of curcumin and diclofenac, an NSAID, in rats. Although curcumin did not produce significant alteration in oral diclofenac bioavailability, this interaction may have therapeutic advantages [63]. Another study on rats also noted that curcumin exhibited a synergistic interaction with a sub-analgesic dose of diclofenac [64].
Clinical studies and relevant review articles are summarized in Table 3. (Table 3) Table 3. Clinical studies and review articles on turmeric and pain management.  Turmeric supplementation improved quality of life scores and led to clinically relevant and statistically significant improvement in global health status, symptom scores (fatigue, nausea, vomiting, pain, appetite loss, insomnia), and hematological parameters [57].

Review Articles
Eke-Okoro, U. J. et al. The studies provide evidence for the efficacy of about 1000 mg/day of curcumin in treating arthritis. However, due to the insufficient total number of RCTs in this analysis, the methodological quality of the primary studies, and total sample size, a definitive conclusion can not be made. Further rigorous and larger studies are required to confirm the efficacy of turmeric in treating arthritis [70].

Omega-3 Fatty Acids
The effects of polyunsaturated fatty acids (PUFA) in reducing pain has been the focus of many studies. A dietary intake of n-3 series PUFA was demonstrated to help treat pain in conditions such as rheumatoid arthritis, neuropathy, dysmenorrhea, and inflammatory bowel disease. In patients with chronic pain, the levels of n-6 series polyunsaturated fatty acids are high, indicating a possible role in pain regulation [71]. One of the body's natural omega-3 fatty acids (O3FA) is eicosapentaenoic acid (EPA, Figure 4) which can be found in various types of algae as well as in fish inhabiting cold deep waters. Studies have shown adding EPA to the diet can reduce the severity and frequency of migraine headaches likely by inhibiting prostaglandin levels and serotonin activity [72].
Based on studies and the prescribing information of O3FA, it may enhance the antiplatelet activity of drugs such as aspirin and naproxen and it is recommended to monitor the patients [73,74]. This is mediated by affecting platelet function and altering the interaction between platelets and the vascular wall [75]. Some animal studies have investigated the interaction between O3FA and drug products. For instance, the combination of O3FA and morphine in animal studies showed an additive anti-nociceptive effect, even showing analgesic activity at a sub-therapeutic dose of morphine. Moreover, chronic co-administration attenuated the development of tolerance to morphine [78]. Docosahexaenoic acid (DHA, Figure 4), a type of O3FA, has been studied in combination with drugs such as diclofenac. Animal studies on this combination attributed synergistic interaction at a systemic level in terms of nociception, inflammation and gastric security [79]. A similar study found that DHA combined with naproxen affords supra-additive nociception and gastric safety [80]. The same authors also noted synergistic anti-nociception and gastric safety with the combination of DHA with the NSAID indomethacin [81].
Clinical studies and relevant review articles are summarized in Table 4. (Table 4)

Capsaicin
Capsaicin ( Figure 5) is a natural chili pepper extract and its topical application is an established treatment option for various pain conditions [92]. Intense or repetitive exposure to capsaicin leads to a reversible and selective loss of nociceptive nerve endings. It specifically opens the nonselective cation ion, transient receptor potential cation channel subfamily V member 1 (TRPV1) also known as vanilloid receptor, predominantly found in C-fiber polymodal nociceptors. The influx of cations into the neurons leads to a transient burst of action potentials, leading to a profound burning, stinging, mechanical and thermal hyperalgesia. It is followed by reversible desensitization which can last for several weeks. This effect of capsaicin is referred to as "defunctionalization". While pain receptors regenerate in 4 to 16 weeks, the pain fibers cannot transmit pain signals, resulting in a long-term decrease in sensitivity of mechanical, thermal, and noxious stimulation [93,94]. A randomized controlled trial found that supplementing topical diclofenac with capsaicin offered superior pain relief compared to diclofenac alone, but not compared to capsaicin alone [95]. In fact, topical capsaicin is well-tolerated in combination and no drug interactions have been noted so far [96]. Its cutaneous patches containing 8% capsaicin is approved in the European Union for the treatment of non-diabetic neuropathic pain [92,98].
Clinical studies and relevant review articles are summarized in Table 5. (Table 5)   There was no statistically significant difference between the experimental and placebo groups. The factor of time had a major effect on the non-specific improvement of the assessed parameters and the placebo effect had an important role in treating the patients with TMJ pain [114].

Thunder God Vine
Thunder god vine is also known as Tripterygium wilfordii Hook F (TwHF) is a traditional Chinese herb. With its anti-inflammatory, immunosuppressive, and analgesic effects, it has been used for rheumatoid arthritis (RA) joint pain and insect pests [124,125]. It inhibits the expression of proinflammatory cytokines, proinflammatory mediators, adhesion molecules, and matrix metalloproteinases by lymphocytes, macrophages, synovial chondrocytes, and fibroblasts [126].
Oral TwHF has been associated with several adverse events including renal insufficiency, dysmenorrhea, decreased male fertility, hematotoxicity, embryotoxicity, and immune suppression demonstrated by an increased rate of infections. TwHF has a high risk-benefit ratio as its subacute toxicity demonstrated pathological changes in the reproductive and lymphatic systems [127]. It is recommended not to take TwHF with other immunosuppressive meds.
Triptolide (Figure 6), an active component of TwHF, has demonstrated strong analgesic activity. Fluoxetine, an antidepressant used in the treatment of chronic pain, in combination with triptolide was shown to produce a significantly stronger analgesic effects than the use of fluoxetine alone, in an animal study [128]. A study done in the rat neuropathic pain model showed that the combination of triptolide and MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, produced synergistic analgesia, as well as inhibition of signaling pathways induced by chronic neuropathic pain [129]. Figure 6. Chemical structures of triptolide [130] and celastrol [131].
It is worth noting that celastrol (Figure 6), another active component of TwHF, was found to signal through the cannabinoid receptor-2, a target of interest in drug development for pain relief [132].
Clinical studies and relevant review articles are summarized in Table 6. (Table 6) While T. wilfordii has beneficial effects in reducing rheumatoid arthritis symptoms, due to its association with serious adverse events, we cannot recommend its use [125].

Butterbur
Butterbur is the root extract of Petasites hybridus, a perennial shrub that was used since ancient times for its medicinal properties such as fever, wound healing, muscle spasm, and migraine prophylaxis. The active agents are likely its sesquiterpenes such as petasin and isopetasin (Figure 7) [72,134]. Isopetasin can activate transient receptor potential ankyrin 1 (TRPA1) channels, resulting in neuropeptide containing nociceptor excitation and consequently heterologous neuronal desensitization. Petasites may also act through calcium channel regulation and peptide-leukotriene biosynthesis inhibition. These effects on pain and neurogenic inflammation may count for its role as an anti-migraine treatment [72,135].  [136] and isopetasin [137].
Its preparation is very important considering its leaves contain a high concentration of pyrrolizidine alkaloids, which are hepatotoxic and carcinogenic. The most common adverse events of butterbur are mild gastrointestinal symptoms and belching [134].
Petadolex, a butterbur extract with clinically proven efficacy against migraines has been associated with cases of herbal-induced liver injury. Among the most severe incidences, 50% of patients were co-medicating with NSAIDs or zolmitriptan, which may have contributed or even elicited liver injury. [138]. The potential hepatotoxicity of butterbur has been associated with the pyrrolizidine alkaloids, which were removed from many commercially available presentations [139][140][141]. Pyrrolizidine alkaloids are metabolized to toxic metabolites by CYP3A4, so concomitant administration of CYP3A4 inducers may enhance the toxicity of butterbur [142].
Special extracts of the rhizomes of butterbur were found to inhibit of prostaglandins E 2 and COX-2 release by direct interaction with the enzymes [143]. This suggests an additive effect when combined with certain NSAIDs.
Clinical studies are summarized in Table 7. (Table 7)

Feverfew
Feverfew constitutes the dried leaves of the weed plant Tanacetum parthenium. Several centuries ago it was used to treat fever, headaches, and inflammation. It was rediscovered in the late 20th century for migraine headaches. Its active agents are the parthenolide (Figure 8) within the leaves. It can inhibit serotonin release from white blood cells and platelets, and prevent platelet aggregation. It can also have anti-inflammatory action by inhibiting phospholipase A and prostaglandin synthesis [72]. Adverse events documented in clinical trials include mouth ulcers, gastrointestinal disturbances, and joint aches [72]. By inhibiting platelet aggregation and secretion it can increase the risk of bleeding when used concomitantly with other antiplatelet or anticoagulant agents such as naproxen. Therefore, therapy modification is recommended [22].
Feverfew was found to strongly inhibit the activity of CYP3A4, the most abundant cytochrome found in livers and small intestines, responsible for the metabolism of more than 50% of the currently used therapeutic drugs [149].
Clinical studies and relevant review articles are summarized in Table 8. Only five of the six trials reported on migraine frequency outcome. All studies were either of high or unclear risk of sample size bias. Due to uncommon outcome measures and heterogeneity between the studies in terms of interventions, design, and participants, a pooled analysis of the findings was not possible. Three trials with small sample sizes reported a positive effect of feverfew. Two rigorous trials did not report a significant difference between feverfew and placebo groups. In conclusion, larger rigorous trials using stable feverfew extracts are needed before a firm conclusion can be drawn [154].

Willow Bark
Willow bark extract is one of the first examples of modern medication development from an herbal drug. It is obtained from the willow tree also known as Salix, and is generally standardized to salicin (Figure 9) but may contain other salicylates as well as flavonoids and polyphenols. It has been used for thousands of years for its antipyretic, analgesic, and anti-inflammatory effects [155,156]. The active agents of willow bark extract inhibit COX-2 mediated release of prostaglandins E 2 and the release of interleukin 1ß and tumor necrosis factor-α [157]. The most common reported adverse events are gastrointestinal disturbances, allergic reaction to salicylates, and children are at risk of Reye's syndrome. It should be avoided in pregnant females as salicylates can cross the placenta and are eliminated slowly in newborns. There is an increased risk of bleeding and concomitant treatment with other salicylate-containing medication increases these risks and therapy should be monitored or modified [155,159]. NSAIDs also have the potential to interact with herbal supplements that are known to possess antiplatelet activity, such as willow bark [160]. Nonetheless, no relevant drug interactions were reported in a trial on the aqueous willow bark extract STW 33-I, in patients allowed to co-medicate with NSAIDs and opioids [161]. The incidences of hepatotoxicity and nephrotoxicity may be augmented by acetaminophen when concomitantly used with herbs containing salicylate, such as willow bark [160].
Clinical studies and relevant review articles are summarized in Table 9. (Table 9) Table 9. Clinical studies and review article on willow bark and pain management.

Discussion
Pain is one of the most common conditions for which patients in the United States turn to CAM. In turn, one of the most commonly sought forms of CAM is herbal medicine. These therapeutic avenues are often underreported or undisclosed to medical professionals, which may cause risks to the patients. CAM are not only largely unregulated, but their efficacy and safety are often poorly understood. Herbal medicines in particular often contain combinations of active components, and their sourcing presents possible risks related to contamination with toxins. Additional risks come from combination therapy, as some herbal medicines have been shown to affect the safety and efficacy of conventional medicines found over-the-counter or prescribed by physicians. Our review aims to consolidate efficacy and safety data for some of the most commonly used herbal medicines for pain management; by identifying the active components to which are attributed analgesic effects, integrating clinical trial data on their effectiveness, and relating known herb-drug interactions.
Herbal medicines are often used with little physician knowledge or guidance. A better understanding of the active ingredients and mechanisms of action of common herbal medicines can guide practitioners to modify their treatment plans, determine appropriate use, anticipate toxicities, and prevent possible adverse herb-drug interactions for patients. Chronic pain can become debilitating, and patients are often motivated to seek alternative treatment, including herbal medicine. While self-management has been recognized as part of a successful overall treatment strategy for patients suffering from chronic pain [3], it is important for physicians to be able to optimize and integrate herbal medicines and, if needed, other CAM into the care they provide.
The largely unregulated status of herbal medicines may present safety issues. In particular, herbal medicines are often taken alongside synthetic drugs, enabling herbdrug interactions with poorly studied clinical outcomes. Concurrent use of agents with similar pharmacological effects such as anti-inflammatory, hepatotoxic, anti-platelet, or anticoagulation should be approached with caution and if needed the patient should be monitored or the treatment plan should be modified. In fact, drug classes most likely to interact with herbs are antiplatelets, anticoagulants, sedatives, antidepressants, and antidiabetics [22]. Concurrent use of ginger, turmeric, omega-3 fatty acid, feverfew, and willow bark with agents that predispose to bleeding, can enhance their effect and increase the risk of bleeding. Therefore, the patients should be monitored and if needed the treatment plan should be modified. Other commonly noted interactions are due to herbal medicines modulating the expression and activity of cytochromes. Nonetheless, there are also instances of additive or synergistic outcomes from herb-drug interactions.
With the popularity of herbal medicine growing annually, our review provides a summary and an overview of available data on the common herbs of interest used as alternatives for pain management. However, further rigorous scientific and systematic inquiries are necessary to be able to validate or refute the clinical claims made for herbal medicine.