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 medicine ²), 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

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 platelets ³⁹ 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

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.