Herbal and Nutritional Supplements for Painful Conditions

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20 Herbal and Nutritional Supplements for Painful Conditions

Andrea H. Zengion, ND, MSAOM, Eric Yarnell, ND

Herbs and supplements are widely used by patients in pain.1 Throughout this chapter, mechanisms of action and efficacy, dosing, and safety information will be provided for each herb, supplement, and natural product for the pain syndromes for which research literature supports their use. For herbs, the medicinal portion of the plant will also be given because different parts of a plant may have different constituents and clinical effects. This chapter is meant to provide an overview, and practitioners not already trained in natural medicine should seek additional education to become proficient in the use of natural products.

Natural substances offer many potential benefits for helping treat patients with pain. First, they often have long histories of use (thousands of years in some cases; the Ebers Papyrus, arguably the oldest book in the world, consists of a materia medica of traditional Egyptian medicine2), and one could argue these substances are among the best tested and most “evidence-based” medicines available.3 Second, they are largely nontoxic, although there are exceptions.4 One study found that over a 10-year period, only two deaths in the United States could be linked to herbal medicines.5 Third, they are often cost effective, again, with exceptions. Finally, they act on multiple pathways, some of which are not addressed by any other existing therapies.6 Study of the mechanism of action of some natural treatments has led to breakthroughs in the understanding of pain pathophysiology and to the development of entirely new categories of medications. For example, investigation of capsaicin brought about enhanced understanding of vanilloid receptors, TRPV1, unmyelinated C fibers, substance P, and novel topical treatments for pain syndromes.7

Western Herbal Medicine: Complexity and Synergy

Herbs have been an important part of Western medicine for thousands of years.8,9 Herbs contain hundreds of different compounds, and traditional medicine theorizes that the constituents of medicinal plants act synergistically.10 Many studies support that complex herbal extracts often have effects that are distinct and/or greater than those of their single isolated constituents.11

In some cases, isolated compounds or highly refined extracts with just a few constituents such as silymarin, a complex of three flavonoligans from Silybum marianum (milk thistle) seed, or curcumin, a mixture of three resinous polyphenols from Curcuma longa (turmeric) rhizome, are used clinically. It is not clear if these offer advantages over more complex, less concentrated extracts, given a near total lack of comparative studies, but such extracts do satisfy the demand for uniformity, simplicity, and patentability prevalent in a market-driven health care system and society.12 Throughout this chapter, both refined and crude herbal extracts will be listed for completeness, although often it is unknown which form is superior (Table 20-1).

Table 20-1 Summary of Herbs and Supplements Used for Treatment of Pain

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Chinese Herbal Medicine: Ancient and Modern

Chinese medicine is one of the most ancient healing systems on the planet.13,14 Based on a distinctive physiology quite unlike Western medicine, it is still in use today. Herbs play a central role in Chinese medicine, although acupuncture is more widely accepted in Western society. Unlike in Western cultures, herbs in traditional Chinese medicine are almost always given in complex formulas,15 as it was observed that combining herbs produces a stronger, more specific therapeutic effect, and that herbs used together mitigate some of the adverse effects they may engender as single entities. Formulation is still the most common way to prescribe Chinese herbs.16 Nevertheless, biochemical and pharmaceutical research techniques have been extensively applied to Chinese herbs, and now single-herb medicines or isolated constituents extracted from single herbs are used more widely. Caution is warranted with these much more recent innovations, and the traditional formulas are preferred in most cases. Many of these same arguments could be made about traditional medicine systems from around the world, such as Ayurveda and Unani-Tibb in South Asia, or Native American medicine.

Antiinflammatory Herbal Medicines

Curcuma Longa (Turmeric)

The rhizome of Curcuma longa is ground or tinctured (1:2 ratio, >45% ethanol content)6 to make medicine. Most supplements use curcumin, a mixture of lipophilic polyphenolic compounds including diferuloylmethane, demethoxycurcumin and bisdemethoxycurcumin found in the rhizome. It is traditionally used for pain and has been shown to modulate inflammatory cytokines including IL-1β, IL-12, IL-6, TNF-α, and IFN-γ.17

Osteoarthritis: In the treatment of knee osteoarthritis pain, the efficacy and safety of Curcuma were found to be comparable to those of ibuprofen.18
Rheumatoid arthritis: Curcumin inhibited proliferation of, and induced apoptosis in, the synovial fibroblasts of rheumatoid arthritis (RA) patients in vitro.19
Dosage: 1 to 10 g powdered rhizome three to five times per day or tincture (1:1 or 1:2) 3 to 10 mL three to five times per day. 500 to 2000 mg curcumin three to five times per day.
Cautions/contraindications: Patients on anticoagulant therapies should not be given doses of Curcuma longa in excess of 15 g per day. Turmeric (but not curcumin extracts) contains large quantities of oxalate and should be taken with high-fiber and high-calcium foods to avoid exacerbation of kidney stones.20 Per German Commission E monographs, it should not be given in cases of biliary obstruction.21

Bromelain

Bromelain is a mixture of enzymes derived from pineapple. Its effects are mainly a product of its proteolytic activity, which stimulates fibrinolysis by increasing plasmin, but bromelain also has been shown to prevent kinin production and to inhibit platelet aggregation.22 Because its mechanism of action is generally antiinflammatory, rather than specific to a particular disease process, bromelain is used to treat a variety of pain and inflammatory conditions. When given to treat pain, it must be administered away from food because it will act as a digestive enzyme if consumed with food.

Sports medicine: A study examining the effects of a mixture of proteases, including bromelain, after downhill running concluded that these enzymes improved post-workout recovery of contractile function and attenuated duration of muscle soreness compared to placebo.23 Another study comparing placebo to ibuprofen and to bromelain in a trial of eccentric exercise (weightlifting) found that neither ibuprofen nor bromelain improved delayed onset muscle pain (elbow flexor soreness), range of motion or concentric peak torque compared to placebo.24
Arthritic and knee pain: Bromelain improves functionality and decreased pain in mild acute knee pain and knee osteoarthritis.25 In one study, efficacy of treatment with a bromelain-rutoside-trypsin product compared favorably to treatment with diclofenac.26 A review article found bromelain effective for treatment of knee and shoulder osteoarthritis, but reported varying degrees of patient tolerance to high doses. Adverse effects included diarrhea, flatulence, nausea, dry mouth, unspecified allergic reaction, and skin irritation.27
Wound healing: Bromelain may be useful postsurgically to shorten healing time and to reduce levels of edema, pain, and ecchymoses.28
Dosage: 500-2000 mg three or more times per day (potency of 2400 mcu or 3200 gelatin dissolving units (gdu) per 1000 mg) away from food.
Cautions/contraindications: Animal studies indicate that bromelain inhibits fibrinogen synthesis and increases fibrinolytic activity.29 Although bromelain has not been shown to increase risk of bleeding, this result is theoretically possible.

Omega-3 Oils

Omega-3 essential fatty acids are used by the body to form cell membranes and antiinflammatory prostaglandins, among other important molecules. Murine studies indicate that these fats produce resolvins and protectins, novel lipids with antiinflammatory properties. Although these fatty acids do not act specifically on nociceptive pathways, their administration has the well-documented effect of reducing inflammation in the body.30

Fish oils are a major source of omega-3 fatty acid supplementation, especially of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are direct precursors of series three prostaglandins. Flax oil also contains a high proportion of α-linolenic acid, which is itself a precursor to DHA and EPA, but requires enzymatic conversion before having a direct antiinflammatory effect and is, therefore, less efficient for this purpose. Because of this, DHA and EPA have stronger and more direct antiinflammatory effects.

A study comparing two marine oils (seal and cod liver oils) found no difference in their efficacy,31 suggesting that the origin of the fatty acids is less important than their EPA/DHA content. Fatty acid source is a concern with regard to heavy metal and PCB content of the supplements, and only products that employ third-party verification of purity should be given.

Exercise tolerance: A study examining post-exercise pain in men who were not part of a regular training program found that administration of omega-3 fatty acids reduced pain and improved range of motion 48 hours after exercise.32
Myocardial and skeletal muscle membranes take up omega-3 fatty acids at a higher rate than other organs. A study of fish oil administration showed that this incorporation results in decreased myocardial oxygen consumption with the same degree of performance; lower resting heart rate; and decreased episodes of arrhythmias. In skeletal muscle, fish oil administration resulted in increased insulin sensitivity and efficiency.33
Arthritides: A Cochrane meta-analysis of patients with rheumatoid arthritis or joint pain secondary to dysmenorrhea or inflammatory bowel disease found significant reduction in patient-reported pain, NSAID consumption and number of painful joints. The authors concluded that benefit is likely for osteoarthritis patients as well, although clinical trials are still needed.30
Dosage: 6 to 9 g fish oil providing 1.8 g EPA per day minimum. At least 3 months of treatment is usually required to see therapeutic effect.
Caution/contraindication: Caution: May cause bruising in some individuals. Data are varied as to whether or not omega-3 fatty acids inhibit clot formation. One study found that omega-3 acids potentiate the effects of dual antiplatelet therapy (aspirin and clopidogrel).34 A placebo-controlled study examining interactions between omega-3s and warfarin found that 3 to 6 g of fish oil given daily did not produce a statistically significant difference in PT-INR.35 Contraindication: Some sources give a contraindication for omega-3 fats presurgically because of their possible anticoagulant effects.

Angelica sinensis (Dang Gui, Tang Kui, Dong Kuai)

The root is used as medicine and the herb is tinctured, decocted, or powdered and encapsulated. In China, it is also injected locally into areas of low back and postsurgical pain with significant improvement of symptoms.36 Angelica is commonly used in Chinese medicine for gynecologic complaints, including dysmenorrhea. Active constituents include ligustilide, which has been demonstrated in murine studies to be antinociceptive and antiinflammatory.37

General pain: A controlled clinical trial found that Angelica improved pain and intensity during cold pressor testing.38
Dysmenorrhea: Aqueous and ethanol extracts of Angelica tend to stimulate the uterus, whereas the essential oil inhibits its contraction. Interestingly, studies have shown that administering the herb to a contracted uterus results in relaxation, whereas administering it while the uterus is relaxed results in contraction. In traditional Chinese medicine, decoction is the most common mode of administration, but a study in which the essential oil was given reported a 76% reduction in dysmenorrhea.36
Dosage: 4.5 to 15 g dried root per day in divided doses.
Caution/contraindications: Contraindications: Should not be given during pregnancy in women with a history of miscarriage. Traditionally not used in cases of diarrhea or acute viral infection. In one study, Angelica potentiated warfarin’s anticoagulant effects, although the herb does not affect prothrombin time when given alone (and thus may have worked by inhibiting platelet aggregation). Because of these findings, it is theorized that Angelica may interact with other anticoagulants as well.36 In traditional Chinese medicine, it is used after the first trimester of pregnancy, although its use in pregnancy is contraindicated altogether in other sources.

Zingiber officinalis (Ginger)

The rhizome of Zingiber has been used in traditional Asian medicines, including Chinese and Ayurvedic herbalism, for millennia. Today, it is administered as encapsulated powder, in decoction, food, or tincture. Ginger is more commonly used for treatment of digestive complaints than it is for pain, but has been shown to inhibit prostaglandin and thromboxane formation in platelets39 and serotonin receptors in vivo. In vitro studies of human synoviocytes have demonstrated that Zingiber extract inhibits TNF-α activation and cyclooxygenase-2 expression.40

Migraines: A product which combined Tanacetum and Zingiber demonstrated effect in aborting incipient migraine when treatment was administered in the headache’s early phases. Results were promising, although the study was of small size.41 No definitive studies have yet been performed, but evidence suggests that Zingiber may be effective in migraine prophylaxis.39
Dysmenorrhea: A double-blind clinical trial found Zingiber to be as effective as ibuprofen in treating pain and reducing severity of dysmenorrhea.42
Arthritides: Study data are mixed, with one showing reduction of symptoms of knee osteoarthritis and another crossover study showing symptomatic improvement of osteoarthritis only before crossover. Some relief of pain and swelling was reported in a retrospective case analysis of rheumatoid arthritis, osteoarthritis, and myalgia patients.40
Dosage: 250 mg-1 g encapsulated, one to four times per day; tincture (1:3 to 1:5) 1 to 5 mL one to four times per day; eaten with food as tolerated.
Caution/contraindications: Caution in gastric diseases such as peptic ulceration, doses of less than 4 g per day in persons on anticoagulant therapies or with risk of hemorrhage. There is a theoretical concern that Zingiber may inhibit clotting, but relatively little data supporting that assertion. One study found that administration of moderate doses (3.6 g powdered rhizome extract per) did not alter PT-INR.43 Another study demonstrated that one 10 g dose of powdered rhizome resulted in decreased platelet aggregation in patients with coronary artery disease.44 A second study found that Zingiber counteracted the antifibrinolytic properties of fatty meals and even increased fibrinolysis.45 Other studies, however, including one in which subjects consumed 15 g of fresh rhizome or 40 g of cooked stem, found no antiplatelet activity in vitro.46

Harpagophytum procumbens (Devil’s Claw)

This herb is native to southern Africa, and it grows in a fairly limited distribution, making it somewhat threatened in the wild. Because of this, only cultivated material should be purchased. The tuber is used therapeutically, and active constituents appear to be iridoid glycosides including harpagosides. This herb is usually administered as an aqueous or alcohol extract. Mechanism of action is unknown, but appears to be mediated via the central nervous system with possible peripheral antinociceptive effects. A rodent study found that its effects were attenuated by naloxone administration, suggesting that it acts at least in part via opioidergic pathways.47

Low back pain: Two studies provided strong evidence that a dose of 50 mg harpagosides per aqueous administration provides short-term relief for low back pain. Another provided moderate evidence that 100 mg harpagosides per aqueous dose effectively reduces low back pain in the long term. Furthermore, 60 mg harpagosides taken daily for short-term treatment of chronic low back pain was as effective as 12.5 mg rofecoxib.48
Dosage: Standardized extract providing 50 to 100 mg harpagosides per day. Tincture (1:2-1:5): 4 to 5 mL three times per day. Liquid extract (1:1): 3 to 4 mL three times daily.
Caution/contraindication: Contraindicated in hyperchlorhydria, acute peptic ulcers, and acute diarrhea. Harpagophytum may potentiate warfarin.21

Boswellia serrata (Frankincense)

Boswellia acts as an antiinflammatory by its inhibition of 5-lipoxygenase, although it has no apparent effect on cyclooxygenase. Because it is a resin, it is relatively hydrophobic and must be tinctured by using a menstruum with high ethanol content. In Chinese herbal medicine, Boswellia carterii, a similar species, is an important herb for treatment of pain and healing of ulcers and is often paired with myrrh. Extracts may be standardized to 37.5% to 65% boswellic acids (considered to be the active constituents), although it may also be taken as crude herb in pill or capsule form, or, in Chinese herbal medicine, used topically or added in small amounts to decoctions of other herbs. Adverse effects may include gastrointestinal symptoms because tannins are sometimes difficult to digest.

Osteoarthritis: B. serrata increases joint flexion and reduces pain in knee osteoarthritis. Compared to valdecoxib, Boswellia’s therapeutic activity had a slower onset but persisted longer (valdecoxib’s effects did not persist after cessation of therapy, whereas the Boswellia group maintained improvement up to 1 month after cessation). Boswellia administration resulted in statistically significant improvement of pain, stiffness, and ability to perform daily activities.49 A double-blind, placebo-controlled clinical trial for 5-loxin, a Boswellia extract enriched with 30% 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) found that, administration of the drug resulted in statistically significant reduction of pain, improvement of functional ability, and reduction in levels of matrix metalloproteinase-3 in synovial fluid. Diarrhea, abdominal pain, nausea, mild fever, and weakness were reported as adverse effects.50
Collagenous colitis: A small study demonstrated greater clinical remission rate with administration of Boswellia extract than with placebo after 6 weeks of treatment.51
Dosage: 150 to 400 mg boswellic acid taken three times daily.
Caution/contraindications: Caution: may cause contact dermatitis or mild diarrhea or urticaria.21

Tanacetum parthenium (Feverfew)

The leaf is typically used as medicine and is eaten fresh or taken as tea, encapsulated crude herb or tincture. It appears to act by inhibiting formation of prostaglandins in the arachidonic acid pathway, inhibiting serotonin and histamine secretion, preventing platelet aggregation, or by reducing vascular response to vasoactive amines. Parthenolide is supposedly one of the major active constituents and appears to inhibit arachidonic acid release, but studies using parthenolide alone do not yield the clinical results obtained by administration of the whole herb.52

Migraine: Feverfew has been shown to decrease frequency and severity of migraines when used as a prophylactic, including in a double-blind, randomized, controlled trial.53 A study that used a high-percentage (90%) ethanol extraction did not demonstrate efficacy against migraines, suggesting that such a high proportion of ethanol does not adequately extract the constituents necessary for therapeutic effect. As a consequence, crude herb, aqueous extracts or extracts with an ethanol content below 90% are more likely to have positive clinical effect.6 Additionally, like many pharmaceutical treatments for migraines, patients sometimes present with rebound migraine, sleep symptoms, and anxiety after withdrawal from long-term T. parthenium use.52
Although most studies examine Tanacetum’s use as a migraine prophylactic, a small study demonstrated that product containing Tanacetum and Zingiber demonstrated effect in aborting incipient migraine when treatment was administered in the headache’s early phases.52
Dosage: 25 to 225 mg per day. Tincture (1:2 or 1:3) 3 to 5 mL three times per day for prevention and up to 10 to 12 mL five times a day for acute treatment. Patients may chew one to three fresh leaves daily for migraine prophylaxis, although mouth ulcers are occasionally reported with this administration.
Caution/contraindications: Caution in allergy to members of the Asteraceae (Compositae) and during pregnancy because it may stimulate uterine contraction.52

Centrally-Acting Herbs and Supplements

Corydalis yanhusuo

A member of the poppy family, Corydalis yanhusuo is one of traditional Chinese medicine’s chief herbs for relieving pain. The rhizome is used. Like many Chinese herbs, it is traditionally taken as an aqueous extract (i.e., decocted as tea, although it is also given as tincture [1:3 to 1:5]) or in pill or capsule form. Substitution of other species of Corydalis for C. yanhusuo is not recommended because their actions appear to differ. Its primary active constituents are alkaloids, including berberine, corydaline, and tetrahydropalmatine. Various studies have compared Corydalis extracts to morphine and findings vary, indicating that they have from 1% to 40% the analgesic effect of morphine.16,22,54

General pain: A controlled clinical trial found that Corydalis improved pain and intensity during cold pressor testing.38 Besides its antinociceptive effects, Corydalis may be especially suited to generalized pain in cancer. On its own, Corydalis exhibits antimetastatic, antiproliferative, and antiangiogenic activity in vitro, the latter apparently via inhibition of the VEGF pathway.55 A study of the synergistic effects of Corydalis and Curcuma wen-yujin found that combining the herbs in a 3:2 ratio had stronger anticancer effects than either components used singly.56
Dysmenorrhea: A study of corydaline found it effective in relieving dysmenorrhea in 73% of subjects.22
Dosage: Crude herb, decocted: 4.5 to 12 g per day, divided doses. Tincture: (1:2 to 1:5) 0.25 to 1 mL three times daily.6
Caution/contraindication: In Chinese medicine, this herb is generally contraindicated during pregnancy.16

Cannabis sativa

The active constituents of Cannabis sativa (marijuana) are primarily cannabinoids, found in the greatest quantity in the flowering/fruiting tops of the plant. Many cannabinoids have been identified, the most well-known of which is tetrahydrocannabinol (THC). As an herb, Cannabis is most commonly taken by smoking or vaporizing, eating the plant, often in other foods, or via oromucosal sprays or capsules. The herb itself is illegal under United States federal law, although some states permit its prescription. Many studies performed on Cannabis have used a synthetic form of THC (most notably dronabinol [Marinol]) or other cannabinoids such as cannabidiol (CBD), although whole herb administration and plant extracts have also been studied.

Research into the mechanism of cannabinoid receptors in the body is ongoing, but suggests that they play a role in the pain-mediating effects of cannabinoids. Two major types of receptors, CB1 (found primarily in the nervous system, both centrally and peripherally) and CB2 (found in nonnervous tissues, including immune cells), have been identified.57

Acute postsurgical pain: A dose-escalation study showed that 10 mg of Cannabis extract (with defined THC and CBD content in a 1:0.5 ratio) administered postsurgically provided rescue analgesia after opioid administration had been discontinued.58
Neuropathic pain: Some studies of cannabinoid treatment in end-of-life pain management have also been performed, often by using dronabinol. Cannabis has also been shown to improve muscle and nerve in HIV patients and the cannabinoid CT-3 was shown to have effect on neuropathic pain in end-of-life care.53 Cannabinoids were also found to be effective in managing neuropathic pain59 in conditions such as diabetic neuropathy,60 brachial plexus avulsion,61 and multiple sclerosis62 (in which cannabinoids have also been seen to subjectively improve symptoms of spasticity).63
Improved sleep: At least two studies also show increased sleep quality with Cannabis administration, which is likely to be of benefit in pain management.7
Rheumatoid arthritis: A preliminary placebo-controlled trial found that a standardized Cannabis extract (2.7 mg THC and 2.5 mg CBD per dose) significantly reduced symptoms of pain and inhibited disease progression in rheumatoid arthritis.64
Severe pain management: Opioids are regarded as the most effective therapy for severe pain, but adverse effects and tolerance may pose significant problems with their use. Besides the analgesic effects of Cannabis, which occur on a pathway independent of that of the opiates, it may also be used in concert with opioids to treat severe pain. Non-psychoactive doses of THC may act as opiate-sparing agents, just as THC acts synergistically with opioids and mediates effects of opioid tolerance. This may allow for reduced dosing of opiates to treat major pain and fewer adverse effects of tolerance.65,66
Dosage: Further study is necessary to establish dosing guidelines.
Contraindications: Use of Cannabis, especially in adolescents and people at risk for mental illness, may be related to onset of psychological diseases such as psychosis or schizophrenia.67,68
Cautions: Although dosage has not been well-established, a study examining the effects of smoking Cannabis on capsaicin-induced pain demonstrated hyperalgesia at high Cannabis doses,69 suggesting that a therapeutic window should be established. Caution in patients with hepatitis C is warranted because Cannabis smoked daily may hasten progression of hepatic fibrosis.70

Hypericum perforatum (St. John’s Wort)

The aerial parts of the plant are used as medicine. Hypericum may be given internally as a tincture, decoction, or encapsulation, or used topically as a lotion. Hypericin, hyperforin, and flavonoids are thought to be the major active constituents. This herb is most commonly associated with treatment of depression but eclectic physicians used it topically as a vulnerary and internally to treat neurogenic pain, including sciatica and rheumatic pain.71

Two murine studies demonstrated antinociceptive properties of H. perforatum. These properties are dose-dependent in a bell-shaped trend, i.e., therapeutic effect may only be derived from doses that are neither too low nor too high. Hypericum’s mechanism of nociceptive action seems to be due to hypericin’s inhibition of protein kinase C and to interaction with opioid receptors, although other receptor classes may be involved.72 Opioid receptor involvement is supported by the finding that the herb significantly enhances the effects of concurrently administered morphine without altering serum morphine levels.47

Otitis media: An herbal ear drop, of which Hypericum was the primary analgesic herb, was as effective as an ametocaine (tetracaine)/lidocaine ear drop in relieving pain of acute otitis media.73 A double-blind, randomized study of the same product found that it was more effective used alone than with amoxicillin. This latter finding supports the use of the herbal formula as a topical treatment in acute otitis media. Pain is largely self-limiting, and current American Academy of Otolaryngology-Head and Neck Surgery guidelines recommend topical treatment as first-line therapy for this condition.74
Burning mouth syndrome: Encapsulated Hypericum reduced the number of sites of pain in stomatodynia (a condition thought to have a strong association to depressive symptoms), although the pain itself, measured by VAS scoring, was not ameliorated.75
Neuropathy: A murine study reported that even a single dose of dried Hypericum extract significantly reduced neuropathic pain in both constriction injury and chemically-induced pain.76 A human study found that Hypericum had no effect on neuropathy,77 but as the authors of the murine noted, the human neuropathy trial likely used a dose (in that study, 2700 mcg of a product called totalhypericin) of Hypericum that exceed the window of efficacy; Hypericum’s antinociceptive activity seems to follow a bell-shaped trend.76
Dosage: Tincture: (1:2 to 1:5) 2 to 4 mL three or more times per day. Decoction: 2 to 4 g dried herb taken three or more times per day. Standardized extract: 300 mg three or more times daily providing 0.3% hypericin and 5% hyperforin.
Caution/contraindications: Hypericum decreased circulating warfarin levels in a study of healthy volunteers via its effects on cytochrome P450 enzymes, leading to lower PT-INR and increased risk of clot formation in such patients. Hypericum does not affect baseline INR, only heparin clearance.78 Caution: Hypericum upregulates cytochrome P450 3A4 and possibly 2C9 and P-glycoprotein. It has been shown to reduce serum levels of drugs metabolized by P450 3A4 in the gut, although study data are limited. Drugs for which an interaction has been shown include anti-HIV protease inhibitors, cyclosporine, atorvastatin, simvastatin, finasteride, digoxin, and many others.79 In addition, the herb may reduce the efficacy of oral contraceptives; during Hypericum administration, other modes of back-up contraception should be considered. Hypericin-containing medicines may have photosensitizing effects at high doses and in very light-skinned people, although the doses recommended generally do not cause a problem.12 If there is a concern about this problem, wearing sunscreen will reduce the already low risk to nearly zero.

Bryonia alba (White Bryony)

The root is usually tinctured to make medicine and has traditionally been used for pleurisy, pain, and other inflammatory conditions. Bryonia dioica (red bryony) has the same effects as B. alba and may be substituted. This herb is prescribed in low doses only and is toxic in high concentrations. Gastric distress is the most common early sign of toxicity, although cardiac toxicity may result from excessive administration.

Dosage: (1:10) one drop in approximately 120 mL three times daily.
Caution/contraindications: Contraindicated in children, pregnancy, lactation, renal failure, and hepatic failure.6

Topical Herbs and Supplements

Capsicum frutescens (Cayenne)

Capsaicin is the major active constituent of the cayenne pepper, Capsicum frutescens and Capsicum annuum. It is chiefly applied topically, either in patches or in ointment form. Commercial creams or ointments are available in 0.025% and 0.075% capsaicin concentrations. Capsaicin works as a counterirritant. It stimulates small-diameter pain fibers, thereby depleting them of substance P and preventing transmission of pain signals from the peripheral to the central nervous system.22 In studies of treatment for peripheral neuropathy, for instance, patients experienced benefit after 4 to 6 weeks of use, although a high-dose topical patch resulted in immediate improvement in one study.80 Some studies concluded that capsaicin was a poor therapy but application of capsaicin was observed only for 3 or 4 weeks. Patients may experience adverse effects on initial use.

Successful treatment with capsaicin has been most commonly reported in conditions affecting topical nerves, including postherpetic neuralgia,53 diabetic neuropathy, arthritis, mouth pain following chemotherapy and radiation, postmastectomy pain, and trigeminal neuralgia. However, capsicum has also been used to successfully treat cluster headaches after intranasal application.81

Dosage: Typically requires application two or three times a day or pain sensation may return.
Contraindications: Capsaicin causes topical irritation on initial application, but this almost always passes with frequent use. The irritation is almost never severe. To achieve a therapeutic effect, patients must often overcome an initial period of discomfort before desensitization has occurred. Avoid contact with mucous membranes if not indicated for treatment.

Urtica dioica (Stinging Nettle)

All parts of the Urtica plant are used as medicine, although only the leaves are used to treat pain. Fresh leaves are used topically for pain as a counterirritant. Urtica leaves are covered with fine hairs with a high silicon content that break when touched and release a toxin into the skin. Like apitherapy, therapeutic effect is achieved by stinging the affected area (urtication). The toxin contains several chemicals including histamine, acetylcholine, and serotonin, and provokes urticaria and C fiber discharge.82

Joint pain: A double-blind, crossover trial of patients with chronic base-of-thumb pain due to osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis found that urtication resulted in decreased disability levels and pain symptoms.83
Dosage: Topical: apply fresh leaf to affected area for approximately 30 seconds two or three times. Repeat as needed.
Caution/contraindications: Theoretically, internal use may decrease efficacy of warfarin due to nettle leaf’s substantial vitamin K content.71

Symphytum officinale (Comfrey)

Herbalists have long used Symphytum root and leaf topically and internally for treatment of pain and osseous fractures. Symphytum is available in cream, ointment, and gel forms for topical use. Active constituents include rosmarinic acid, mucopolysaccharides, allantoin, and mucilage. The discovery of unsaturated pyrrolizidine alkaloids (uPA), which are potentially hepatotoxic and carcinogenic, in Symphytum has led to the recommendation that this herb be used only topically and on intact skin. uPA are absorbed only very minimally during dermal application. The herb is still used internally for short periods because studies indicate that the alkaloids cause genetic damage only in long-term use (several months or more).71,84 uPA-free extracts may be used indefinitely.

Back pain: Topical Symphytum (250 g herb to 100 g cream) resulted in significantly decreased levels of pain with active motion, at rest and on palpation in patients with upper and lower back pain. The effect was strongest with higher doses, and treatment was well tolerated in all patients.85
Osteoarthritis: An ointment containing liquid extract of Symphytum root (1:2) brought about significant reduction in pain scores for knee osteoarthritis in a double-blind, placebo-controlled trial.86
Dosage: 1-2 g cream applied topically three to five times per day.
Caution/contraindications: uPA-containing extracts pose a minor risk of hepatotoxicity and carcinogenicity, although these alkaloids show only minimal transdermal absorption. uPA-free extracts pose no such risk. Do not apply to large areas of broken skin.

Arnica montana

The Arnica flower is used topically for treatment of pain and is not generally taken internally (except in homeopathic form) because of its potential toxicity. It is available commercially in gels and ointments for topical use. Active constituents include sesquiterpene lactones, flavonoids, and volatile oils.

Bruising: A rater-blinded study of 20% topical Arnica ointment found that the ointment decreased bruise healing time more than did petrolatum jelly or 1% vitamin K/0.3% retinol mixture.87
Osteoarthritis: A gel preparation of Arnica tincture was as effective in relieving hand osteoarthritis pain as ibuprofen.88
Dosage: Apply topically 3 to 5 times per day.
Caution/contraindications: Not to be taken internally or applied to broken skin or near the mouth. Contraindicated in pregnancy in physiologic doses. Homeopathic topical preparations do not pose risk of toxicity in pregnancy.

Dimethyl Sulfoxide (DMSO)

DMSO is an organic solvent with a variety of pharmaceutical actions, including analgesic, diuretic, bacteriostatic, membrane-penetrant, antiinflammatory, vasodilatory, and cholinesterase inhibitory effects.89 Data about DMSO’s analgesic effects on its own are mixed. However, when DMSO is used as a carrier for other analgesics, it increases these agents’ efficacy (in one study, lidocaine,90 in another, diclofenac)91 and reduces their morbidity.

CRPS: DMSO is recommended for type I CRPS, in particular the warm type, concurrent with therapeutic exercise. Weaker evidence suggests that it may be of benefit for type II CRPS.
Dosage: Applied topically five times per day.92
Caution/contraindications: May cause skin irritation.

Echinacea spp. (Purple Coneflower)

The aerial parts of Echinacea may be tinctured and used as a gargle. Besides its use as an antimicrobial, extracts of Echinacea can have a numbing effect and may be used to treat pharyngeal pain. An Echinacea/sage throat spray was found to be as effective and as well-tolerated as chlorhexidine/lidocaine in treatment of acute sore throats.93

Dosage: Throat spray: Two puffs every 2 hours for duration of symptoms. Tincture of fresh root (1:2 to 1:3) 3 to 5 mL in water as a gargle (then swallow) every 2 hours for duration of symptoms.
Caution/contraindications: Contraindication in allergy to members of the Asteraceae (Compositae) family.

Salicylate-Containing Herbal Medicines

Salix alba (White Willow)

The bark of Salix alba is used for pain. Other Salix species, including S. daphnoides and S. purpurea, have a higher salicylate content, but S. alba is the most well-studied of the genus and of the salicylate-containing herbs in general.

Low back pain: A Cochrane review showed moderate evidence that a 240 mg dose of salicin relieves acute exacerbations of chronic back pain and produced the same results as 12.5 mg rofecoxib.94 Effect on nonspecific low back pain is dose-dependent, with the best response seen with a 240 mg dose compared to 120 mg.94
Osteoarthritis: Salix bark extract showed benefit in relieving pain of hip and knee osteoarthritis. After 3 weeks, results were comparable to standard treatment (which was not described), and after 6 weeks, results with Salix were superior to that of the standard treatment. Mild pain complaints responded better than did those that were more severe.95
Dosage: Standardized extract providing 120-240 mg salicin per day in divided doses. Fluid extract (1:1): 2 to 4 mL three times per day or more. Tincture (1:2): 3 to 5 mL three to five times per day.
Contraindications: Salicylate allergy. There is no evidence that willow causes or promotes Reye’s syndrome; indeed, the evidence that aspirin causes the disease is weak or nonexistent.96

Populus tremuloides (Quaking Aspen)

This bark of this tree and leaves contain salicylate glycosides related to those found in willow. Although they have been shown to decrease inflammation in vitro, human trials are lacking.97,98

Hypnotic Analgesic Herbs and Supplements

Valeriana officianalis (Valerian)

Although Valeriana is more commonly associated with treatment of insomnia, it has also traditionally been used for treatment of general pain and headache.6,99

Dosage: Tincture (1:2 or 1:3) 3 to 5 mL three times daily with 5 to 10 mL at bedtime, 1:2 to 1:3 extract. Standardized extract: (0.5% essential oil) 500 to 1000 mg three times per day and at bedtime.
Cautions/contraindications: Occasionally, Valeriana may cause agitation.6

Piscidia piscipula, P. erythrina (Jamaican Dogwood)

Used traditionally to treat pain, these Piscidia species are antispasmodic, hypnotic, and anodyne. The medicinal part, the root bark, is taken as a crude herb, tinctured or administered as an aqueous extract. Aqueous extract appears to be the most potent of the extractions.100 Active constituents primarily appear to be rotenoids and isoflavones, the latter category including piscidone, piscerythrone, and tetrahydroxy-methoxy-diisoprenyl-isoflavone (DPI).

These herbs are commonly used in medical herbalist practice, for example for migraine, dysmenorrhea, rheumatic pain, neuralgia, sciatica, and spastic pain, but few human studies have been performed to evaluate their use. Animal studies demonstrate that the fluid extract decreases the amplitude of intestinal contractions.101 DPI, piscidone and piscerythrone had spasmolytic effects against oxytocin-induced contractions in rat uteri.102

Symptoms of toxicity include sweating, numbness, tremors, and excessive salivation.

Dosage: Crude root bark (dried): 2 to 4 g three times daily. Tincture: (1:3 to 1:5) 1 to 3 mL three or more times per day.
Caution/contraindications: Caution: Dosing simultaneously with other sedative therapies, as Piscidia may amplify these effects. Contraindication: pregnancy, bradycardia, and cardiac insufficiency.

Eschscholtzia californica (California Poppy)

The aerial parts of the plant have been used as a hypnotic anodyne traditionally. Its hypnotic effects have been confirmed in the research literature, but few comprehensive clinical studies have been performed on Eschscholtzia to examine its role in pain management. It is taken internally, most commonly as a tincture or decoction.6 Although a member of the Papaveraceae family, it is traditionally regarded as one of the safest and most gentle of the anodynes and may be given to children.103

Dosage: Tincture (1:2): 3 to 5 mL three or more times per day.
Caution/contraindications: German Commission E monographs indicate a caution for use in pregnancy because cryptopine, a minor constituent, causes uterine stimulation in animal studies. No such activity, however, has been observed after administration of Eschscholtzia.21

Nutritional Cofactors

Methylsulfonylmethane (MSM)

MSM is produced by the adrenal glands and may be obtained in the diet from some fruits and vegetables.

Arthritides: MSM shows weak pain-relieving effect on its own but is more frequently given in conjunction with glucosamine with or without chondroitin. Animal studies showed that it decreased joint degeneration. Thus far, human studies showed modest effects on pain and swelling, but no effect on stiffness.104
Dosage: 1000 to 3000 mg three times per day.
Caution/contraindications: None currently noted.

Riboflavin

This B vitamin serves a variety of metabolic roles. With regard to pain control, its mechanism is similar to that of coQ10 in that it facilitates mitochondrial energy metabolism.

Migraine: High-dose riboflavin (400 mg per day) reduced frequency of attacks and number of days of migraine duration.105,106
Dosage: 400 mg per day.
Caution/contraindications: None.

Lipoic Acid/Alpha Lipoic Acid/Thioctic Acid

Lipoic acid is a disulfide produced in the body. It is a small, easily absorbed molecule and is a potent antioxidant that increases the activity of catalase and superoxide dismutase in peripheral nerves, is neurogenerative and normalizes endoneural blood flow. Because it is both lipophilic and hydrophilic, it addresses both fat- and water-soluble free radical species. It is administered orally and intravenously. Coadministration of a B-complex supplement is recommended because lipoic acid may deplete these vitamins.107

Migraine prophylaxis: Thought to have an effect similar to riboflavin and coQ10, thioctic acid showed within-group improvement in headache days, frequency, and severity of migraines in one study.108 Research is ongoing, and anecdotal reports are favorable.53
Diabetic neuropathy: A critical review of several clinical trials of varying sizes found that intravenous lipoic acid significantly improved major symptoms of diabetic polyneuropathy, including that of the cranial nerves;53 lower limb motor and sensory nerve conduction; and deficits in nervous function and cardiac autonomic neuropathy. Furthermore, it reversed some of the vascular changes of diabetes, including elevated NF-κB, albuminuria, and elevated thrombomodulin. The analysis did not reveal any major concerns about safety.107 A long-term study (NATHAN I) is being conducted to further assess the role of lipoic acid in treatment of diabetic polyneuropathy.
Dosage: 600 to 1800 mg orally per day in divided doses; 600 mg daily intravenously.
Caution/contraindications: May worsen paresthesias when treatment is first begun. May decrease blood glucose levels.53

S-adenosyl methionine (SAM-e)

SAM-e is the stable salt form of S-adenosyl methionine, a methyl donor produced from methionine and adenosine triphosphate in the liver. It is commonly used to treat depression, a condition in which CSF SAM-e levels tend to be low, compared to nondepressed individuals.109 SAM-e increases turnover of serotonin and may increase levels of dopamine and norepinephrine.

Osteoarthritis: SAM-e controlled osteoarthritic pain as effectively as celecoxib after 2 months of use in a study comparing the two, although celecoxib controlled pain much better in the first month.104
Fibromyalgia: A double-blind, placebo-controlled Danish study found that 800 mg of SAM-e administered orally improved fatigue, disease activity, morning stiffness, mood, and pain experienced during the study’s final week.110
Dosage: 800 to 1600 mg per day in divided dose.
Caution/contraindications: Rare episodes of mania and hypomania have been reported in depressed patients taking SAM-e. Drug-herb interactions may occur with concurrent administration of serotonergic drugs, levodopa, or monoamine oxidase inhibitors.

Glucosamine Sulfate and Chondroitin Sulfate

Although they are not anodynes in the same sense as other remedies listed here, glucosamine sulfate and chondroitin sulfate are useful in the treatment of osteoarthritis pain because of their effect on joint structure. Glucosamine is a substrate for the glycosaminoglycans that comprise hyaluronic acid, a chief component of joint tissue.

Chondroitin plays a number of roles in connective tissue synthesis. It is itself a glycosaminoglycan and, when hydrated, it creates osmotic pressure that increases the compressive resistance of synovial cartilage. It also stimulates the production of collagen and proteoglycan and inhibits enzymatic destruction of the synovium.22,111

Osteoarthritis: Numerous studies have been performed to evaluate the efficacy of glucosamine and chondroitin administration for osteoarthritis treatment with mixed results, although this may be due to combining different forms of the agents, or to some studies’ use of less effective forms of glucosamine and/or chondroitin or products with poor standardization.53 Industry bias may also account for some of the discrepancy between studies, although it should also be noted that many of the studies not funded by industry sources examined glucosamine hydrochloride.112 According to a meta-analysis, glucosamine sulfate used alone relieved pain due to osteoarthritis and prevented disease progression.113 Glucosamine hydrochloride, although cheaper, is not effective for osteoarthritis.114 Conclusions derived from studies of one form cannot be extrapolated to apply to the other form, even though data for glucosamine sulfate are mixed.115
Chondroitin treatment reduced pain, swelling, and effusion, and maintained or improved joint space and serum osteocalcin levels. Glucosamine sulfate and chondroitin sulfate taken together decreased pain and joint effusion in moderate-to-severe arthritis pain, but results were inconsistent between studies.111,116
Dosage: 1500 mg glucosamine sulfate per day. 400 to 1200 mg chondroitin sulfate per day.
Caution/contraindication: Contraindication for glucosamine: shellfish or iodine allergy. Glucosamine may increase PT-INR when given with warfarin.117 Chondroitin may also increase the effects of anticoagulant therapies. Because of its structural similarities to heparin, some sources recommend that it be contraindicated in pregnancy.118

Magnesium

Used clinically for a wide range of conditions, magnesium is given in a variety of forms, including magnesium citrate, glycinate, and oxide. Food sources include green leafy vegetables, whole grains, nuts, and seeds.

Pediatric migraine: An intention-to-treat analysis of magnesium oxide administration found a significant reduction in migraine days compared to placebo.119
Dysmenorrhea: Magnesium likely inhibits prostaglandins and was found to be superior to placebo in the treatment of dysmenorrhea.120
Dosage of elemental magnesium: Children: 9 mg/kg/day; Adults: 250 to 600 mg per day in divided doses, to bowel tolerance.
Caution/contraindications: Magnesium citrate supplements can have an osmotic laxative effect at high doses. This effect may be seen to a lesser degree in other forms.

Hormonal Analgesics

Melatonin

Research on melatonin has examined the hormone’s influence on nonendocrine tissues and has elucidated the mechanism by which it might influence pain. It is present throughout the central nervous system, and has been shown to treat acute, inflammatory, and neuropathic pain symptoms.121

Migraines/headaches: Melatonin levels are frequently low in migraineurs and cluster headache patients.122 Many of the symptoms of migraine prodrome seem to originate in the hypothalamus, which exerts regulatory input over the pineal gland and its melatonin production. Melatonin is also present in significant amounts in the trigeminal ganglion, which may also be involved in migraine initiation. It is unknown if melatonin plays a direct role in headache pathogenesis, or if decreased melatonin simply is another sign of hypothalamic dysfunction, but melatonin treatment has been shown to ameliorate headache symptoms in some individuals,123 especially those with clear circadian dysregulation (i.e., delayed sleep phase syndrome).22
Postoperative analgesia: A randomized, placebo-controlled study found that patients undergoing elective prostatectomy who were given 6 mg melatonin the night before and 1 hour before surgery had less pain, used less intraoperative fentanyl, required less tramadol, and had better postoperative sleep than the placebo group. The treatment group, however, had greater extubation time and took longer to recover from anesthesia.124
Dosage: 1 to 20 mg, generally taken only at bedtime or just before a painful procedure.
Caution/contraindications: May cause daytime grogginess and delayed recovery from anesthesia.

Vitamin D

Although vitamin D is a nonessential vitamin, recent research has demonstrated epidemic deficiency of this vitamin in the general population, especially in the elderly, institutionalized populations, those who live in northern latitudes, with limited sun exposure or who have dark skin. It is available in pill, capsule, powder, and liquid forms. Vitamin D deficiency has been linked with a variety of painful disease states, including bone loss and attendant fractures,125 pelvic floor disorders,126 systemic lupus erythematosus,127 tuberculosis, certain cancers, and inflammatory bowel diseases.128 A 2008 review article, however, found that studies demonstrating a link between hypovitaminosis D and chronic pain were largely of poor quality and that too few randomized controlled trials had been performed.129 Although vitamin D2 (ergocalciferol) and D3 (cholecalciferol) are both available commercially, the D3 form of the vitamin is more potent and has longer-lasting effects.130

Vitamin D intoxication is reported rarely, and published cases all involve persons who consumed at least 40,000 IU per day long-term. Evidence suggests that the currently accepted No Adverse Effect Limit of 2000 IU per day is probably too low “by at least five fold.” No adverse effects are seen in individuals who are not hypersensitive when serum levels of 25(OH)D are less than 140 nmol/L (56 ng/mL), which is attained in healthy people by consuming 10,000 IU per day long term.131 Another study whose subjects’ serum concentrations reached 400 nmol/L reported no observable hypercalcemia, hypercalciuria or adverse effects.132 Although dosages of 10,000 IU per day may be taken long-term without major problems, very large single doses of vitamin D are not recommended. A study in which a massive single dose of vitamin D (500,000 IU) was given to women older than age 70 with normal baseline serum levels demonstrated that such high doses increased the risk of fracture and falling.133

Osteomalacia: Supplemental vitamin D is crucial to treatment of osteomalacia, as hypovitaminosis D is a key component of the disease’s pathogenesis. Pain may worsen before improvement is seen following treatment.134
Diabetic neuropathy: Type 2 diabetics are commonly deficient in vitamin D. Repletion of vitamin D levels in these patients resulted in significant reduction of neuropathic pain. Pain scores were negatively correlated with serum 25(OH)D levels, although no correlation between pain and serum iPTH levels was observed.135
Low back pain: A study of 360 Saudi Arabian men and women with low back pain of no obvious etiology found that 83% had deficient levels of vitamin D.136 Another reported a similar finding among Egyptian women.137 However, treatment was not performed as part of either study.
Rheumatoid arthritis: A vitamin D receptor has been identified on human immune cells. In its capacity as a hormone, vitamin D seems to downregulate autoimmunity caused by excessive Th-1 activity. Serum 25(OH)D levels are inversely correlated with disease activity in rheumatoid arthritis. People with autoimmune diseases may have a higher vitamin D requirement to maintain optimum serum levels.138,139
Myalgia in statin-treated patients: 92% of statin-treated patients with concurrent myalgia/myositis and hypovitaminosis D saw resolution of myalgia/myositis after 12 weeks of 50,000 IU vitamin D per week (the form of the vitamin given was not identified).140
Migraine: Case studies report successful treatment of menstrual and postmenopausal migraine with vitamin D and calcium, although no large-scale studies have so far been performed.141,142
Multiple sclerosis: The Nurses’ Health Study demonstrated that women whose serum vitamin D levels were in the highest quintile were 40% less likely to develop multiple sclerosis.138
Dosage: Vitamin D3, or cholecalciferol, is the preferred form. Recommended daily allowances are 200 to 600 IU per day, depending on age, with a maximum safe level of 2000 IU per day, but evidence suggests that doses necessary to treat deficiency and even to maintain normal levels are much higher (5,000 to 20,000 IU per day). Due to interactions between these vitamins in vivo, it is recommended to give high-dose vitamin D with small amounts of vitamins A and K.143
Therapeutic dose: 1000 to 10,000 IU per day long term. Weekly doses of 50,000 IU are also given, usually for shorter durations (e.g., 4 to 6 weeks).
Caution/contraindications: Contraindications: Hypercalcemia, hyperphosphatemia, vitamin D toxicity, and sarcoidosis. Caution in calcium oxalate nephrolithiasis.

Coenzyme Q10 (CoQ10)

Coenzyme Q10 acts as a mitochondrial electron-transport chain cofactor in the reactions that produce ATP. It scavenges free radicals and is a component of the Krebs cycle enzyme succinate dehydrogenase-coQ10. Its alternate name, ubiquinone, reflects its omnipresence throughout the body. Despite the fact that coQ10 is synthesized innately, it is commonly deficient in the general population.22 Its production decreases with age and it is depleted by many pharmaceuticals, including beta blockers, antipsychotics, some statins, metformin, sulfonylureas, and some tricyclic antidepressants.118 Animal studies demonstrate that its antinociceptive effects may be a consequence of its downregulation of nitric oxide.144 Two forms are available commercially—ubiquinone and ubiquinol (ubiquinone’s reduced form). Ubiquinol is more commonly given clinically.

Migraines: CoQ10 deficiency may be a predisposing factor in the incidence of migraine headaches.145 Prophylactic coQ10 supplementation in adult migraineurs146 and repletion of coQ10 in pediatric migraineurs with low serum levels decreased migraine frequency.147
Chronic Fatigue Syndrome: Although the role of oxidative stress and mitochondrial dysfunction in chronic fatigue syndrome is controversial, coQ10 levels were found to be low in such patients. Supplementation may improve symptoms of chronic fatigue syndrome.148
Dosage: Pediatric: 1 to 3 mg/kg/day. Adults: 150 mg/day with food.
Caution/contraindications: Antagonizes warfarin and other anticoagulants, may increase effect of hypotensives.118

Miscellaneous Agents

Ginkgo biloba (Ginkgo)

Ginkgo is most commonly prescribed for vascular disorders, including those pertaining to perfusion of the central nervous system. The leaves are used in Western herbalism, and the seed kernel is used in traditional Chinese herbal medicine. Active constituents include ginkgolides A, B, C, and J (all diterpene lactones), bilobalide (a sesquiterpene lactone), and flavonol glycosides. Ginkgo is available as tincture, capsules, tablets, decoction, and standardized extract—usually in solid form. The standardized extract is the most well-researched preparation and contains 24% to 32% flavonoids and 6% to 12% terpenoids. The standardized extract form is the most recommended by some sources because proportions of active constituents may vary widely between different samples of crude herb.

Migraine: A preliminary trial found that an extract containing ginkgolide B reduced frequency and duration of migraine attacks in adults.149 Another preliminary trial found that Ginkgolide B given prophylactically with coQ10, vitamin B2 and magnesium reduced frequency and need for pain medication in a small group of pediatric migraineurs.150
Raynaud’s phenomenon/disease: A standardized extract of Ginkgo was effective in reducing number of attacks in patients with Raynaud’s phenomenon compared to placebo.151 Anecdotal evidence also suggests effectiveness in Raynaud’s disease of the nipple during lactation.
Intermittent claudication: A 2000 meta-analysis found that Ginkgo extract was slightly more effective than placebo in increasing walking distance, although not as effective as vasodilators.152 A more recent Cochrane review, however, found that Ginkgo offered no benefit in treatment of this condition.153
Dosage: Standardized extract: 120 to 240 mg per day, in divided doses.
Caution/contraindications: Ginkgo should be discontinued at least 36 hours prior to surgery. It may interact additively with other anticoagulants.71 Drug-herb interactions are possible with a number of other pharmaceuticals, including anticonvulsants, antidepressants, cyclosporine, and thiazide diuretics.

Centella asiatica (Gotu Kola)

Centella has been used in traditional herbal medicines across Asia. The whole plant is used, and dosage forms include encapsulation of the crude herb, decoction, and tinctures. Active constituents include triterpenoid saponins and notable amounts of asiaticoside, madecassoside and madecassic acid. A murine study demonstrated that the crude herb possesses antiinflammatory and antinociceptive properties. Its effects were likely mediated by the central and peripheral nervous systems and its mechanism of action may involve opioid receptors.154

Venous insufficiency: Centella has been used traditionally for its circulatory effects. A triterpene fraction of Centella given to patients with venous hypertension decreased symptoms of edema, pain, fatigue, and restless limb more effectively than placebo. Capillary filtration rate was also decreased, as was ankle circumference, in patients receiving the Centella extract.155
Dosage: 180 mg per day of total triterpenic fraction. Tincture or glycerite of fresh plant (1:2 to 1:3) 3 to 5 mL three or more times per day. Topical cream 1-2 g two or more times per day.
Caution/contraindications: Caution in patients with cholestasis, celiac disease, fat malabsorption disorders, and deficiency of fat-soluble vitamins due to Centella’s high saponin content.21

Viburnum opulus (Cramp Bark), Viburnum prunifolium (Black Haw)

The bark of both species is used medicinally and may be decocted, tinctured, or encapsulated as crude herb. Viburnum opulus contains hydroquinones, coumarins, and tannins, whereas Viburnum prunifolium’s primary constituents include coumarins, biflavones, and phenolic acids.

Dysmenorrhea: Both Viburnum species treat dysmenorrhea, although classically, V. opulus is used for pain radiating into the thighs and V. prunifolium is specific for severe low back pain with a feeling of bearing down in the pelvis. Animal studies demonstrate that both herbs have relaxant effects on the uterus, and this effect has also been described in humans in studies of V. prunifolium.156
Dosage: V. opulus: Tincture: 5 to 10 mL (1:5) three times per day. Encapsulated or decocted crude herb: 2 to 4 g three times per day. V. prunifolium: Tincture: (1:3 to 1:5) 5 to 10 mL (1:5) three times per day. Encapsulated or decocted: 2.5 to 5 g three times per day.
Cautions/contraindications: Caution: V. prunifolium is also used to treat hypertension; use caution in hypotensive patients. This herb also contains oxalates but is generally given in doses far too low to warrant caution in patients with calcium oxalate nephrolithiasis.

Scutellaria laterifolia (Skullcap)

Scutellaria baicalensis (Huang qin)

This herb has been part of traditional Chinese materia medica for millennia and is used to treat pain and inflammatory conditions. Its active constituents include baicalin, a flavonoid, the herb’s most studied component.

Osteoarthritis: A short-term, randomized, double-blind study found that a supplement (flavocoxid, given 500 mg twice per day) combining baicalin and catechin (a flavan derived from Acacia catechu) was as effective as naproxen in treating osteoarthritic knee pain. The mechanism of action is likely inhibition of COX-2, LOX-5 and NF-κB.157
Dosage: Dried herb: 1 to 2 g three times per day. Liquid extract (1:2): 0.6 to 1.5 mL three times per day. Tincture (1:5): 1 to 2 mL three times per day.6
Caution/contraindications: Not to be used for extended periods during pregnancy.21

Rosa canina

The fruit is used medicinally and is taken internally as a decoction, alcohol extract, powder, or encapsulated. Rosa fruits generally contain high concentrations of vitamin C, although their antioxidant properties result from other components as well.

Osteoarthritis: A clinical trial of a powder made from Rosa canina was found to reduce osteoarthritic pain compared to placebo.158 A meta-analysis found Rosa powder to be twice as likely as placebo to reduce pain.159
Dosage: 4 to 5 g powder twice daily.
Caution/contraindications: None currently known.

Solidago chilensis (Brazilian Arnica)

The leaves and flowers of Solidago have long been used as medicine by indigenous Brazilians. Active constituents include flavonoids, carotenes, and diterpenoids. Mouse studies demonstrate that the rhizome also possesses potent antiinflammatory activity.160

Low back pain: In a small, placebo-controlled study, Solidago improved lumbar flexibility and reduced pain when applied topically in gel form. The majority of the subjects experienced absence of pain with treatment.161
Dosage: 10 g gel applied topically twice daily.
Caution/contraindications: Allergy to members of the Asteraceae family.

References

1. Bücker B., Groenewold M., Schoefer Y., Schäfer T. The use of complementary alternative medicine (CAM) in 1 001 German adults: Results of a population-based telephone survey. Gesundheitswesen. 2008;70(8-9):e29-e36.

2. Ebbell B. The Papyrus Ebers: The Greatest Egyptian Medical Document. Copenhagen: Levin & Munskgaard; 1937.

3. Court W.E. A history of herbal medicine. Pharm Hist (Lond). 1985;15(2):6-8.

4. Yang S., Dennehy C.E., Tsourounis C. Characterizing adverse events reported to the California Poison Control System on herbal remedies and dietary supplements: A pilot study. J Herb Pharmacother. 2002;2(3):1-11.

5. Woolf A.D., Watson W.A., Smolinske S., Litovitz T. The severity of toxic reactions to ephedra: Comparisons to other botanical products and national trends from 1993-2002. Clin Toxicol (Phila). 2005;43(5):347-355.

6. Yarnell E. Phytotherapy for the treatment of pain. Modern Phytotherapist. 2002;7(1):3-12.

7. Kam P.C.A., Hayman M. Capsaicin: A review of its pharmacology and clinical applications. Curr Anaesthes Crit Care. 2008;19:338-343.

8. Becky L.Y. De Materia Medica by Pedianus Dioscorides. Hildesheim, Germany: Olms-Weidmann. 2005.

9. Scarborough J. Theophrastus on herbals and herbal remedies. J Hist Biol. 1978;11(2):353-385.

10. Spelman K. Philosophy in Phytopharmacology: Ockham’s Razor versus Synergy. J Herb Pharmacother. 2005;5:31-47.

11. Ma X.H., Zheng C.J., Han L.Y., et al. Synergistic therapeutic actions of herbal ingredients and their mechanisms from molecular interaction and network perspectives. Drug Discov Today. 2009;14(11-12):579-588.

12. Brinker F.J. Complex Herbs, Complete Medicines. Sandy, Ore: Eclectic Medical; 2004.

13. Zheng B.C. Shennong’s herbal—one of the world’s earliest pharmacopoeia. J Tradit Chin Med. 1985;5(3):236.

14. Liu Z.Z. Shen Nong’s Herbal, the earliest extant treatise on Chinese materia medica. Zhong Yao Tong Bao. 1982;7(5):43-45.

15. Hou J.P. The development of Chinese herbal medicine and the Pen-ts’ao. Comp Med East West. 1977;5(2):117-122.

16. Bensky D., Clavey S., Stöger E. Chinese herbal medicine materia medica, 3rd ed. Seattle: Eastland Press; 2004.

17. Bright J.J. Curcumin and autoimmune disease. Adv Exp Med Biol. 2007;595:425-451.

18. Kuptniratsaikul V., Thanakhumtorn S., Chinswangwatanakul P., et al. Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. J Altern Complement Med. 2009;15(8):891-897.

19. Park C., Moon D.O., Choi I.W., et al. Curcumin induces apoptosis and inhibits prostaglandin E(2) production in synovial fibroblasts of patients with rheumatoid arthritis. Int J Mol Med. 2007;20(3):365-372.

20. Tang M., Larson-Meyer D.E., Liebman M. Effect of cinnamon and turmeric on urinary oxalate excretion, plasma lipids, and plasma glucose in healthy subjects. Am J Clin Nutr. 2008;87:1262-1267.

21. Mills S., Bone K. The essential guide to herbal safety. St Louis: Elsevier; 2005.

22. Pizzorno J.E., Murray M.T. Textbook of Natural Medicine, 3rd ed. St Louis: Churchill Livingstone; 2006.

23. Miller P.C., Bailey S.P., Barnes M.E., et al. The effects of protease supplementation on skeletal muscle function and DOMS following downhill running. J Sport Sci. 2004;22:365-372.

24. Stone M.B., Merrick M.A., Ingersoll C.D., Edwards J.E. Preliminary comparison of bromelain and ibuprofen for delayed onset muscle soreness management. Clin J Sport Med. 2002;12:373-378.

25. Walker A.F., Bundy R., Hicks S.M., Middleton R.W. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults. Phytomedicine. 2002;9:681-686.

26. Akhtar N.M., Naseer R., Farooqi A.Z., et al. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee—a double-blind prospective randomized study. Clin Rheumatol. 2004;23:410-415.

27. Brien S., Lewith G., Walker A., et al. Bromelain as a treatment for osteoarthritis: A review of clinical studies. Evid Based Complement Alternat Med. 2004;1:251-257.

28. MacKay D., Miller A.L. Nutritional support for wound healing. Altern Med Rev. 2003;8:359-377.

29. Lotz-Winter H. On the pharmacology of bromelain: An update with special regard to animal studies on dose-dependent effects. Planta Med. 1990;56:249-253.

30. Goldberg R.J., Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain. 2007;129:210-223.

31. Brunborg L.A., Madland T.M., Lind R.A., et al. Effects of short-term oral administration of dietary marine oils in patients with inflammatory bowel disease and joint pain: A pilot study comparing seal oil and cod liver oil. Clin Nutr. 2008;27:614-622.

32. Tartibian B., Maleki B.H., Abbasi A. The effects of ingestion of omega-3 fatty acids on perceived pain and external symptoms of delayed onset muscle soreness in untrained men. Clin J Sport Med. 2009;19:115-119.

33. Peoples G.E., McLennan P.L., Howe P.R., Groeller H. Fish oil reduces heart rate and oxygen consumption during exercise. J Cardiovasc Pharmacol. 2008;52:540-547.

34. Gajos G., Rostoff P., Undas A., Piwowarska W. Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: The OMEGA-PCI (Omega-3 fatty acids after PCI to modify responsiveness to dual antiplatelet therapy) study. J Am Coll Cardiol. 2010;55:1671-1678.

35. Bender N.K., Kraynak M.A., Chiquette E., et al. Effects of marine fish oils on the anticoagulant status of patients receiving chronic warfarin therapy. J Thromb Thrombolysis. 1998;5:257-261.

36. Chen JK, Chen TT. Chinese medical herbology and pharmacology. City of Industry, Calif; Art of Medicine; 2004.

37. Du J., Yu Y., Ke Y., et al. Ligustilide attenuates pain behavior induced by acetic acid or formalin. J Ethnopharmacol. 2007;112:211-214.

38. Yuan C.S., Mehendale S.R., Wang C.Z., et al. Effects of Corydalis yanhusuo and Angelicae dahuricae on cold pressor-induced pain in humans: A controlled trial. J Clin Pharmacol. 2004;44(11):1323-1327.

39. Mustafa T., Srivastava K.C. Ginger (Zingiber officinale) in migraine headaches. J Ethnopharmacol. 1990;29:267-273.

40. White B. Ginger: An overview. Am Fam Physician. 2007;75:1689-1691.

41. Cady R.K., Schreiber C.P., Beach M.E., Hart C.C. Gelstat migraine (sublingually administered feverfew and ginger compound) for acute treatment of migraine when administered during the mild pain phase. Med Sci Monit. 2005;11:PI65-PI69.

42. Ozgoli G., Goli M., Moattar F. Comparison of effects of ginger, mefenamic acid and ibuprofen on pain in women with primary dysmenorrhea. J Altern Complement Med. 2009;15:129-132.

43. Jiang X., Williams K.M., Liauw W.S., et al. Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2005;59:425-432.

44. Bordia A., Verma S.K., Srivastava K.C. Effect of ginger (Zingiber officinale Rosc.) and fenugreek (Trigonella foenumgraceum L.) on blood lipids, blood sugar, and platelet aggregation in patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids. 1997;56:379-384.

45. Verma S.K., Bordia A. Ginger, fat and fibrinolysis. Indian J Med Sci. 2001;55:83-86.

46. Janssen P.L., Meyboom S., van Staveren W.A., et al. Consumption of ginger (Zingiber officinale Roscoe) does not affect ex vivo platelet thromboxane production in humans. Eur J Clin Nutr. 50, 1996. 772-724

47. Uchida S., Hirai K., Hatanaka J., et al. Antinociceptive effects of St. John’s Wort, Harpagophytum procumbens and grape seed proanthocyanidins extract in mice. Biol Pharm Bull. 2008;31:240-245.

48. Van Tulder M.W., Furlan A.D., Gagnier J.J. Complementary and alternative therapies for low back pain. Best Pract Res Clin Rheumatol. 2005;19:639-654.

49. Sontakke S., Thawani V., Pimpalkhute S., et al. Open, randomized, controlled clinical trial of Boswellia serrata extract as compared to valdecoxib in osteoarthritis of the knee. Indian J Pharmacol. 2007;39:27-29.

50. Sengupta K., Alluri K.V., Satish A.R., et al. A double blind randomized placebo controlled study of the efficacy and safety of 5-Loxin for treatment of osteoarthritis of the knee. Arthritis Res Ther. 2008;10(4):R85.

51. Madisch A., Miehlke S., Eichele O., et al. Boswellia serrata extract for the treatment of collagenous colitis. A double-blind, randomized, placebo-controlled, multicenter trial. Int J Colorectal Dis. 2007;22:1445-1451.

52. Supernaw RB. Cayenne and feverfew: Popular herbals for pain care. Pain Practitioner. 2000;10:8-9.

53. Rakel D. Integrative Medicine, 2nd ed. Philadelphia: Saunders Elsevier; 2007.

54. Chang H.M., But P.P.H., editors. Pharmacology and Applications of Chinese Materia Medica, vol. 1. Philadelphia: World Scientific, 1986.

55. Gao J.L., Shi J.M., Lee S.M., et al. Angiogenic pathway inhibition of Corydalis yanhusuo and berberine in human umbilical vein endothelial cells. Oncol Res. 2009;17:519-526.

56. Gao J.L., He T.C., Li Y.B., Wang Y.T. A traditional Chinese medicine formulation consisting of Rhizoma Corydalis and Rhyzoma Curcumae exerts synergistic anti-tumor activity. Oncol Rep. 2009;22:1077-1083.

57. Walsh D., Nelson K.A., Mahmoud F.A. Established and potential therapeutic applications of cannabinoids in oncology. Support Care Cancer. 2003;11:137-143.

58. Holdcroft A., Maze M., Doré C., et al. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology. 2006;104:1040-1046.

59. Rahn E.J., Hohmann A.G. Cannabinoids as pharmacotherapies for neuropathic pain: From the bench to the bedside. Neurotherapeutics. 2009;6:713-737.

60. Comelli F., Bettoni I., Colleoni M., et al. Beneficial effects of a Cannabis sativa extract treatment on diabetes-induced neuropathy and oxidative stress. Phytother Res. 2009;12:1678-1684.

61. Berman J.S., Symonds C., Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain for brachial plexus avulsion: Results of a randomised controlled trial. Pain. 2004;112:299-306.

62. Kenner M., Menon U., Elliot D.G. Multiple sclerosis as a painful disease. Int Rev Neurobiol. 2007;79:303-321.

63. Lakhan S.E., Rowland M. Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: A systematic review. BMC Neurol. 2009;9:59.

64. Blake D.R., Robson P., Ho M., et al. Preliminary assessment of the efficacy, tolerability, and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology. 2006;45:50-52.

65. Elikkottil J., Gupta P., Gupta K. The analgesic potential of cannabinoids. J Opiod Manag. 2009;5(6):341-357.

66. Karst M., Wippermann S. Cannabinoids against pain. Efficacy and strategies to reduce psychoactivity: A clinical perspective. Expert Opin Investig Drugs. 2009;18(2):125-133.

67. Dragt S., Nieman D.H., Becker H.E., et al. Age of onset of cannabis use is associated with age of onset of high-risk symptoms for psychosis. Can J Psychiatry. 2010;55(3):165-171.

68. Welch K.A., McIntosh A.M., Job D.E., et al. The impact of substance use on brain structure in people at high risk of developing schizophrenia. Schizophr Bull. 2010 Mar 11. [Epub ahead of print]

69. Wallace M., Schulteis G., Hampton Atkinson J., et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology. 2007;107:785-796.

70. Hezode C., Roudot-Thoraval F., Nguyen S., et al. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology. 2005;42:63-71.

71. Hoffman D. Medical Herbalism. Rochester, Vermont: Healing Arts Press; 2003.

72. Galeotti N., Vivoli E., Bilia A.R., et al. A prolonged protein kinase C-mediated, opioid-related antinociceptive effect of Saint John’s wort in mice. J Pain. 2010;11:149-159.

73. Sarrell E.M., Mandelberg A., Cohen H.A. Efficacy of naturopathic extracts in the management of ear pain associated with acute otitis media. Arch Pediatr Adolesc Med. 2001;155(7):796-799.

74. Sarrell E.M., Cohen H.A., Kahan E. Naturopathic treatment for ear pain in children. Pediatrics. 2003;111(5 Pt 1):E574-E579.

75. Sardella A., Lodi G., Demarosi F., et al. Hypericum perforatum extract in burning mouth syndrome, a randomized, placebo-controlled study. J Oral Pathol Med. 2008;37:395-401.

76. Galeotti N., Vivoli E., Bilia A.R., et al. St. John’s wort reduces neuropathic pain through a hypericin-mediated inhibition of the protein kinase C gamma and epsilon and activity. BiochemPharmacol. 2010;79:1327-1336.

77. Sindrup S.H., Madsen C., Bach F.W., et al. St. John’s wort has no effect on polyneuropathy. Pain. 2000;91:361-365.

78. Jiang X., Williams K.M., Liauw W.S., et al. Effect of St John’s wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol. 2004;57:592-599.

79. Izzo A.A., Ernst E. Interactions between herbal medicines and prescribed drugs: An updated systematic review. Drugs. 2009;69(13):1777-1798.

80. Backonja M., Wallace M.S., Blonsky E.R., et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomised, double-blind study. Lancet Neurol. 2008;7:1106-1112.

81. Fusco B.M., Barzoi G., Agrò F. Repeated intranasal capsaicin applications to treat chronic migraine. Br J Anaesth. 2003;90:812.

82. Alford L. The use of nettle stings for pain. Altern Ther Health Med. 2007;13:58.

83. Randall C., Randall H., Dobbs F., et al. Randomized controlled trial of nettle sting for base-of-thumb pain. J R Soc Med. 2000;93:305-309.

84. Betz J.M., Eppley R.M., Taylor W.C., Andrzejewski D. Determination of pyrrolizidine alkaloids in commercial comfrey products (Symphytum sp.). J Pharm Sci. 1994;83:649-653.

85. Kucera M., Barna M., Horàcek O., et al. Topical symphytum herb concentrate cream against myalgia: A randomized controlled double-blind clinical study. Adv Ther. 2005;22:681-692.

86. Grube B., Grünwald J., Krug L., Staiger C. Efficacy of a comfrey root (Symphyti offic. radix) extract ointment in the treatment of patients with painful osteoarthritis of the knee: Results of a double-blind, randomised, bicenter, placebo-controlled trial. Phytomedicine. 2007;14:2-10.

87. Leu S., Havey J., White L.E., et al. Accelerated resolution of laser-induced bruising with topical 20% arnica: A rater-blinded randomized controlled trial. Br J Dermatol. 2010;163:557-563.

88. Widrig R., Suter A., Saller R., Melzer J. Choosing between NSAID and arnica for topical treatment of hand osteoarthritis in a randomised, double-blind study. Rheumatol Int. 2007;27:585-591.

89. Wein A.J., editor. Campbell-Walsh Urology, 9th ed., Philadelphia: Saunders, 2007.

90. Mohammadi-Samani S., Jamshidzadeh A., Montaseri H., et al. The effects of some permeability enhancers on the percutaneous absorption of lidocaine. Pak J Pharm Sci. 2010;23:83-88.

91. Simon L.S., Grierson L.M., Naseer Z., et al. Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain. 2009;143:238-245.

92. Hegmann K.T., editor. Occupational Medicine Practice Guidelines, 2nd ed. Beverly Farms, Mass: OEM. 2004.

93. Schapowal A., Berger D., Klein P., Suter A. Echinacea/sage or chlorhexidine/lidocaine for treating acute sore throats: A randomized double-blind trial. Eur J Med Res. 2009;14:406-412.

94. Gagnier J.J., van Tulder M.W., Berman B., Bombardier C. Herbal medicine for low back pain: A Cochrane review. Spine. 2007;32:82-92.

95. Beer A.M., Wegener T. Willow bark extract (Salicis cortex) for gonarthrosis and coxarthrosis—results of a cohort study with a control group. Phytomedicine. 2008;15:907-913.

96. Orlowski J.P., Hanhan U.A., Fiallos M.R. Is aspirin a cause of Reye’s syndrome? A case against. Drug Saf. 2002;25(4):225-231.

97. Albrecht M., Nahrsted A., Luepke N.P., et al. Anti-inflammatory activity of flavonol glycosides and salicin derivatives from the leaves of Populus tremuloides. Planta Med. 1990;56:660.

98. von Kruedener S., Schneider W., Elstner E.F. A combination of Populus tremula, Solidago virgaurea and Fraxinus excelsior as an anti-inflammatory and antirheumatic drug. A short review. Arzneimittelforschung. 1995;45:169-171.

99. Vohora S.B., Dandiya P.C. Herbal analgesic drugs. Fitoterapia. 1992;63:195-207.

100. Costello C.H., Butler C.L. An investigation of Piscidia erythrina (Jamaica Dogwood). J Am Pharm Assoc. 1948;37:89-97.

101. Pilcher J.D. The action of certain drugs on the excised uterus of the guinea pig. Arch Intern Med. 1916;18:557.

102. Della Loggia R., et al. Plant flavonoids in biology and medicine II. New York: AR Liss; 1987.

103. Tilgner S. Herbal Medicine from the Heart of the Earth. Creswell, Ore, Wise Acres. 1999.

104. Gregory P.J., Sperry M., Wilson A.F. Dietary supplements for osteoarthritis. Am Fam Physician. 2008;77:177-184.

105. Schoenen J., Jacquy J., Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology. 1998;50:466-470.

106. Boehnke C., Reuter U., Flach U., et al. High-dose riboflavin treatment is efficacious in migraine prophylaxis: An open study in a tertiary care center. Eur J Neurol. 2004;11:475-477.

107. Ziegler D. Thioctic acid for patients with symptomatic diabetic polyneuropathy: A critical review. Treat Endocrinol. 2004;3:173-189.

108. Magis D., Ambrosini A., Sándor P., et al. A randomized, double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis. Headache. 2007;47:52-57.

109. Silveri M.M., Parow A.M., Villafuerte R.A., et al. S-adenosyl-L-methionine: Effects on brain energetic status and transverse relaxation time in healthy subjects. Biol Psychiatry. 2003;54:833-839.

110. Jacobsen S., Danneskiold-Samsøe B., Andersen R. Oral S-adenosyl-methionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1992;20:294-302.

111. Frech T.M., Clegg D.O. The utility of neutraceuticals in the treatment of osteoarthritis. Curr Rheumatol Rep. 2007;9:25-30.

112. Vlad S.C., LaValley M.P., McAlindon T.E., Felson D.T. Glucosamine for pain in osteoarthritis: Why do trial results differ? Arthritis Rheum. 2007;56:2267-2277.

113. Poolsup N., Suthisisang C., Channark P., Kittikulsuth W. Glucosamine long-term treatment and the progression of knee osteoarthritis: Systematic review of randomized controlled trials. Ann Pharmacother. 2005;39:1080-1087.

114. Clegg D.O., Reda D.J., Harris C.L., et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354:795-808.

115. Rozendaal R.M., Koes B.W., van Osch G.J., et al. Effect of glucosamine sulfate on hip osteoarthritis. Ann Intern Med. 2008;148:268-277.

116. Black C., Clar C., Henderson R., et al. The clinical effectiveness of glucosamine and chrondroitin supplements in slowing or arresting progression of osteoarthritis in the knee: A systematic review and economic evaluation. Health Technol Assess. 2009;13(52):1-148.

117. Knudsen J.F., Sokol G.H. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: Case report and review of the literature and MedWatch database. Pharmacotherapy. 2008;28:540-548.

118. Lovett E., Ganta N. Advising patients about herbs and neutraceuticals: Tips for primary care providers. Care. 2010;37:13-30.

119. Wang F., Van Den Eeden S.K., Ackerson L.M., et al. Oral magnesium oxide prophylaxis of frequent migrainous headache in children: A randomized, double-blind, placebo-controlled trial. Headache. 2003;43:601-610.

120. Proctor M.L., Murphy P.A. Herbal and dietary therapies for primary and secondary dysmenorrhoea. Cochrane Database Syst Rev. (3):2001. CD002124

121. Ambriz-Tututi M., Rocha-González H.I., Cruz S.L., Granados-Soto V. Melatonin: A hormone that modulates pain. Life Sci. 2009;84:489-498.

122. Peres M.F., Masruha M.R., Zukerman E., et al. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drugs. 2006;15:367-375.

123. Vogler B., Rapoport A.M., Tepper S.J., et al. Role of melatonin in the pathophysiology of migraine: Implications for treatment. CNS Drugs. 2006;20:343-350.

124. Borazan H, Tuncer S, Yalcin N, et al. Effects of preoperative oral melatonin medication on postoperative analgesqia, sleep quality and sedation in patients undergoing elective prostatectomy: A randomized clinical trial. J Anesth. 2010;24:155-160.

125. Holick M.F. The vitamin D epidemic and its health consequences. J Nutr. 2005;135:2739S-2748S.

126. Badalian S.S., Rosenbaum P.F. Vitamin D and pelvic floor disorders in women: Results from the National Health and Nutrition Examination Survey. Obstet Gynecol. 2010;115(4):795-803.

127. Ruiz-Irastorza G., Egurbide M.V., Olivares N., et al. Vitamin D deficiency in systemic lupus erythematosus: prevalence, predictors and clinical consequences. Rheumatology. 2008;47:920-923.

128. Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutrition. 2003;89:552-572.

129. Straube S, Andrew Moore R, Derry S, et al. Vitamin D and chronic pain. 2009;141:10-13.

130. Armas LA, Hollis BW, Heaney RP. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab. 2004;89:5387-5391.

131. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations and safety. Am J Clin Nutr. 1999;69:842-856.

132. Kimball S.M., Ursell M.R., O’Connor P., Vieth R. Safety of vitamin D3 in adults with multiple sclerosis. Am J Clin Nutr. 2007;86:645-651.

133. Sanders K.M., Stuart A.L., Williamson E.J., et al. Annual high dose oral vitamin D and falls and fractures in older women: A randomized controlled trial. JAMA. 2010;303:1815-1822.

134. Goldman L., Ausiello D., editors. Goldman Cecil Medicine, 23rd ed., Philadelphia: Saunders, 2008.

135. Lee P., Chen R. Vitamin D as an analgesic for patients with type 2 diabetes and neuropathic pain. Arch Intern Med. 2008;168:771-772.

136. Al Faraj S. Al Mutairi K: Vitamin D deficiency and chronic low back pain in Saudi Arabia. Spine. 2003;28:177-179.

137. Lofti A., Abdel-Nasser A.M., Hamdy A., et al. Hypovitaminosis D in female patients with chronic low back pain. Clin Rheumatol. 2007;26:1895-1901.

138. Cutolo M., Otsa K., Uprus M., et al. Vitamin D in rheumatoid arthritis. Autoimmun Rev. 2007;7:59-64.

139. Mouyis M., Ostor A.J., Crisp A.J., et al. Hypovitaminosis D among rheumatology outpatients in clinical practice. Rheumatology. 2008;47(9):1348-1351.

140. Ahmed W., Khan N., Glueck C.J., et al. Low serum 25 (OH) vitamin D levels (<32 ng/mL) associated with reversible myositis-myalgia in statin-treated patients. Trans Res. 2009;153:11-16.

141. Thys-Jacobs S. Vitamin D and calcium in menstrual migraine. Headache. 1994;34:544-546.

142. Thys-Jacobs S. Alleviation of migraines with therapeutic vitamin D and calcium. Headache. 1994;34:590-592.

143. Pizzorno J.E. The path ahead: What have we learned about vitamin D dosing? Integrative Med. 2010;9:8-12.

144. Jung H.J., Park E.H., Lim C.J. Evaluation of anti-angiogenic, anti-inflammatory and antinociceptive activity of coenzyme Q(10) in experimental animals. J Pharm Pharmacol. 2009;61(10):1391-1395.

145. Hershey A.D., Powers S.W., Vockell A.L., et al. Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine. Headache. 2007;47(1):73-80.

146. Rozen T.D., Oshinsky M.L., Gebeline C.A., et al. Open label trial of coenzyme Q10 as a migraine preventative. Cephalagia. 2002;22:137-141.

147. Lewis D.W. Pediatric migraine. Neurol Clin. 2009;27(2):481-502.

148. Cordero M.D., De Miguel M., Moreno Fernàndez A.M., et al. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: Implications in the pathogenesis of the disease. Arthritis Res Ther. 2010;12(1):R17. [Epub ahead of print]

149. D’Andrea G., Bussone G., Allais G., et al. Efficacy of ginkgolide B in the prophylaxis of migraine with aura. Neurol Sci. 2009;Suppl 1:S121-S124.

150. Usai S., Grazzi L., Andrasik F., Bussone G. An innovative approach for migraine prevention in young age: A preliminary study. Neurol Sci. 2010;31(Suppl 1):181-183.

151. Muir A.H., Robb R., McLaren M., et al. The use of Ginkgo biloba in Raynaud’s disease: A double-blind placebo-controlled trial. Vasc Med. 2002;7:265-267.

152. Moher D., Pham B., Ausejo M., et al. Pharmacological management of intermittent claudication: A meta-analysis of randomised trials. Drugs. 2000;59(5):1057-1070.

153. Nicolaï S.P., Kruidenier L.M., Bendermacher B.L., et al. Ginkgo biloba for intermittent claudication. Cochrane Database Syst Rev. 2009;15:CD006888.

154. Somchit M.N., Sulaiman M.R., Zuraini A., et al. Antinociceptive and anti-inflammatory effects of Centella asiatica. Indian J Pharmacol. 2004;36:377-380.

155. De Sanctis M.T., Belcaro G., Incandela L., et al. Treatment of edema and increased capillary filtration in venous hypertension with total triterpenic fraction of Centella asiatica: A clinical, prospective, placebo-controlled, randomized, dose-ranging trial. Angiology. 2001;52(Suppl 2):S55-S59.

156. Hudson T. Women’s encyclopedia of natural medicine, 3rd ed. London: Churchill Livingstone; 2005.

157. Levy R.M., Saikovsky R., Shmidt E., et al. Flavocoxid is as effective as naproxen for managing the signs and symptoms of osteoarthritis in the knee in humans: A short-term randomized, double-blind pilot study. Nutr Res. 2009;29:298-304.

158. Rein E., Kharazmi A., Winther K. A herbal remedy, Herben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis–a double-blind, placebo-controlled, randomised trial. Phytomedicine. 2004;11:383-391.

159. Christensen R., Bartels E.M., Altman R.D., et al. Does the hip powder of Rosa canina (rosehip) reduce pain in osteoarthritis patients?—a meta-analysis of randomized controlled trials. Osteoarthr Cartilage. 2008;16:965-972.

160. Liz R., Vigil S.V., Goulart S., et al. The anti-inflammatory modulatory role of Solidago chilensis Meyen in the murine model of the air pouch. J Pharm Pharmacol. 2008;60:515-521.

161. da Silva A.G., de Sousa C.P., Koehler J., et al. Evaluation of an extract of Brazilian arnica (Solidago chilensis Meyen, Asteraceae) in treating lumbago. Phytother Res. 2010;24:283-287.

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