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FEATURE ARTICLE Treatment of Neuropathic Pain with Plant Medicines Garima Garg and James D. Adams
Prof. James D. Adams
ABSTRACT Neuropathic pain is a common and very prevalent disorder affecting the citizens of both developed and developing countries. The approved and licensed drugs for neuropathic pain are reported to have associated side effects. Traditional plant treatments have been used throughout the world for the treatment of neuropathic pain. Among the many medications and other alternative medicines, several herbs are known to cure and control neuropathic pain with no side effects. The present paper discusses the plants with neuropathic pain and related beneficial effects originating from different parts of world that are of current interest. KEYWORDS neuropathic pain, peripheral neuropathy, medicinal plants
Pain after injury to the nervous system (neuropathic pain) is a major chronic pain condition that remains difficult to treat. Neuropathic pain associated with peripheral nerve injury is characterized by sensory abnormalities such as unpleasant and abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a stimulus that does not normally provoke pain (allodynia). Peripheral neuropathic pain is frequently observed in patients with long standing diabetes, cancer, acquired immune deficiency syndrome (AIDS), leprosy, cervical disc damage and after laminectomy surgery. An experimental model of neuropathic pain is induced by chronic constriction injury to the sciatic nerve and is a widely employed model in experimental animals.(1) It is estimated that 75–150 million people in the United States have a chronic pain disorder. Neuropathic pain is debilitating and often has an associated degree of depression that contributes to decreasing human wellbeing and productivity. Moreover, the management of chronic pain is costly to patients and the health care system.(2) Conventional analgesics like non-steroidal antiinflammatory drugs and opioids are ineffective clinically in attenuating neuropathic pain. Tricyclic anti-depressants (i.e., amitriptyline, nortriptyline and imipramine) and anti-convulsants (i.e., phenytoin, carbamazepine, gabapentin, lamotrigine and topiramate) have been reported to produce anti-allodynic effects in neuropathy. However, these drugs are reported to exhibit a wide spectrum of adverse effects which limits
their full clinical exploitation in the management of painful neuropathy. The most widely used drugs which are approved and licensed for neuropathic pain are: Lyrica (pregabalin), Cymbalta (duloxetine), Neurontin (gabapentin), Lidoderm (5% lidocaine patch), and Qutenza (8% capsaicin patch). They are also associated with a high incidence of side effects.(3) Herbal medicines are reported to be beneficial in the management of painful neuropathy. (1) Below is a list of plants which have the potential to cure neuropathic pain.
Acorus Calamus Acorus calamus belongs to the family Araceae. Traditionally it is used as an ingredient in several drugs employed for the treatment of headache, migraine, body ache, and severe inflammatory pain in the Unani, Ayurveda, and local health care systems in Indian medicine.(4) Phytochemically Acorus species have shown to possess glycosides, flavanoids, saponins, tannins, polyphenolic compounds, mucilage, volatile oil and bitter principles.(5) The essential oil of A . calamus was banned in 1968 in the US due to the
©The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2012 Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90089-9121, USA Correspondence to: Prof. James D. Adams, Tel: 001-323-442-1362, E-mail:
[email protected] DOI: 10.1007/s11655-012-1188-6
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presence of β-asarone, which is considered to be a carcinogen. There is no evidence that β-asarone or preparations of A . calamus cause cancer in humans. β-asarone exists in a cis (E) form and a trans (Z) form. A . calamus essential oil contains several monoterpenoids including (Z)-asarone, (Z)-methyl isoeugenol, (Z)-isoelemicin, (E)-asarone, (E)-methyl isoeugenol, (Z)-beta-ocimene, elemicin, linalool and kessane.(6) (Z)-asarone is the major monoterpenoid making up 81%–92% of the monoterpenoids in the essential oil. Many of these compounds are powerful pain relievers, such as linalool and isoeugenol, since they inhibit transient receptor potential cation channels associated with sensory neurons in the skin. Muthuraman and Singh (7) investigated the protective effects of A . calamus in vincristine induced painful neuropathy. Vincristine significantly induced neuropathic pain manifested in terms of thermal hyperalgesia and allodynia, mechanical hyperalgesia and allodynia, and sciatic functional index along with an increase in the levels of various biochemical indices of pain. A hydroalcoholic extract of rhizomes of A . calamus when administered at the doses of 100 and 200 mg/kg, p.o. for 14 consecutive days was found to attenuate vincristine-induced behavioral and biochemical changes. In an another study, conducted by Muthuraman, et al, (4) the therapeutic potential of hydroalcoholic extracts of rhizomes of A . calamus were studied in tibial and sural nerve transection (TST)-induced neuropathic pain in rats. TST in rats significantly induced thermal hyperalgesia and allodynia, mechanical hyperalgesia, and increased the levels of superoxide anion, total calcium, and myeloperoxidase activity. Oral administration of the extract (100 and 200 mg/kg for 14 days) attenuated TST-induced behavioral, biochemical, and histological changes. This effect may be attributed to its multiple actions including antiinflammatory, antioxidant, and neuroprotective actions. In a similar study, conducted by the same group Muthuraman and Singh,(1) the ameliorative actions of the hydroalcoholic extract of the rhizomes of A . calamus against chronic constriction injury (CCI) of the sciatic nerve-induced peripheral neuropathy in rats was shown. CCI of the sciatic nerve significantly induced thermal, radiant and mechanical hyperalgesia,
and thermal, chemical and tactile allodynia, along with increases in the levels of superoxide anion, total calcium and myeloperoxidase activity. The beneficial effects of the extract may be attributed to its multiple actions including antiinflammatory, antioxidant, and neuroprotective actions.
Artemisia Dracunculus The genus Artemisisa includes more than 1,500 species and is a rich source of herbal remedies in many countries. Several of the species of this genus are used to control diabetes and also have been reported to decrease oxidative stress associated with obesity. These species are also investigated for their antiinflammatory and antinociceptive properties.(8) A . dracunculus contains an essential oil, coumarins, flavonoids and phenolcarbonic acids.(9) The essential oil contains estragole, methyleugenol and other monoterpenoids. Methyleugenol is a powerful pain reliever that inhibits transient receptor potential cation channels. Estragole induces cancer in rats, but has not been banned by in the US. A . dracunculus remains a popular spice in the US. An ethanolic extract of A . dracunculus (PMI-5011) reduced high fat diet induced neuropathy. C57Bl6/J mice were fed high-fat diets for 16 weeks. They developed obesity, moderate nonfasting hyperglycemia, nerve conduction deficits, thermal and mechanical hypoalgesia, and tactile allodynia. Also, the mice displayed 12/15-lipoxygenase overexpression, 12(S)-hydroxyeicosatetraenoic acid accumulation, and nitrosative stress in peripheral nerves and the spinal cord. PMI-5011 (500 mg/kg daily for 7 weeks) normalized glycemia, alleviated nerve conduction slowing and sensory neuropathy, and decreased 12/15-lipoxygenase upregulation and nitrated protein levels in the peripheral nervous system. PMI-5011 proved to be a safe and nontoxic botanical extract which may find use in the treatment of neuropathic changes.(8)
Aconiti Tuber Various species of Aconitum have been used as poisons and medicinals since ancient times. Preparations from certain species of Aconitum of Chinese and Japanese origin have been important drugs in Eastern medicine. These preparations have been used for analgesic, antiinflammatory, anti-rheumatic and neurological indications for centuries.(10) A . carmichaeli is known to contain a number of pharmacologically interesting compounds including monoester-diterpenoid
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alkaloids, diester-diterpenoid alkaloids, lipo-alkaloids (lipoforesaconitine and lipoyunanaconitine), flavonoids (acetylliquiritin), and saponins (gracillin).(11,12) Processed Aconiti tuber (PAT), a traditional oriental herbal analgesic medicine has been evaluated for the relief of neuropathic pain in the rat CCI model.(11) PAT was obtained after treatment of the tuber of A . carmichaeli Debeaux (Iwate, Japan) at 105 ℃ for 50 min to minimize its toxicity. The tuber was dried and reduced to a powder. Further, the powder was suspended in water for oral administration. For this study, 10 to 14 days after CCI the rats received oral PAT at 0.5, 1, 2, 3, or 5 g/kg. Additional groups received oral PAT, 2 g/kg, after pretreatment with intraperitoneal naloxone, intraperitoneal nor-bitaltorphine (norBNI); or intrathecal norBNI. As indicators of mechanical allodynia and thermal hyperalgesia, the pressure threshold of paw withdrawal (PWT) in response to linearly increasing pressure, and latency to paw withdrawal (PWL) in response to radiant heat, were measured before and after drug administration. Oral PAT dose-dependently increased PWT and PWL, which had been decreased due to CCI. The increases in PWT and PWL by oral PAT were inhibited by intraperitoneal and intrathecal norBNI: a selective kappa-opioid receptor antagonist, but not by intraperitoneal naloxone. Thus, it can be concluded that oral PAT can alleviate mechanical allodynia and thermal hyperalgesia, dose-dependently, via spinal kappa-opioid receptor mechanisms in a rat CCI neuropathic pain model.(10)
Cannabis Sativa Cannabis sativa L. has a long history of use both as a medicinal agent and an intoxicant. Several reports highlighted that both the main components of marijuana (C . sativa ), delta-9-tetrahydrocannabinol (THC), a psychoactive component, and cannabidiol (CBD), a non-psychoactive component, display many pharmacological effects. THC has antispasmodic, antitremor, antiinflammatory, appetite stimulant and antiemetic properties. Whereas CBD has antiinflammatory, anticonvulsant, antipsychotic, antioxidant, neuroprotective and immunomodulatory effects.(13) Costa, et al(14) demonstrated for the first time the ability of CBD to alleviate persistent inflammatory and chronic neuropathic pain in rats. The cannabis extract rich in CBD contained 64.5% CBD, 4% THC, 4% of
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other cannabinoids (cannabigerol, cannabichromene, cannabidivarin, cannabidiolic acid) and minor components (terpenes, sterols, triglycerides, alkanes, squalene, tocopherol, carotenoids) was evaluated for an antihyperalgesic effect. Compounds were dissolved in a 1:1:18 mixture of ethanol:cremophor:saline. It was found that the afore mentioned extract containing multiple cannabinoids, in a defined ratio, and other non-cannabinoid fractions (terpenes and flavonoids) provided better antinociceptive efficacy than the single cannabinoid given alone, when tested in a rat model of neuropathic pain. The results also demonstrated that such an antihyperalgesic effect did not involve the cannabinoid CB1 and CB2 receptors. It was mediated by transient receptor potential cation channel vanilloid type 1 receptors. The non-psychoactive compound, cannabidiol, is the only component present at a high level in the extract able to bind to this receptor, thus cannabidiol was probably the drug responsible for the antinociceptive behaviour observed. In addition, after chronic oral treatment with cannabis extract, hepatic cytochrome P450 and intestinal P-glycoprotein were inhibited. The inhibition of hepatic metabolism determined an increased bioavailability of cannabidiol. However, because of the well known antioxidant and antiinflammatory properties of terpenes and flavonoids which could significantly contribute to the therapeutic effects, it can be said that the synergism observed might be achieved also in the absence of the cytochrome P450 inhibition.(15)
Emblica Officinal E . officinalis is one of the myrobalans (fruit bearing plants that exhibit various therapeutic properties) commonly used in triphala (three fruits) preparations. Triphala is a traditional Ayurvedic herbal formulation which is considered an important rasayana (chemical) in Ayurvedic medicine.(16) E . officinalis is highly nutritious and is an important dietary source of vitamin C, minerals and amino acids. The present study targeted oxidative stress mediated nerve damage in diabetic rats using an aqueous extract of E . officinalis , a potent natural antioxidant. Diabetic rats exhibited significantly decreased tail-flick latency in the tail-immersion test (thermal hyperalgesia) and decreased PWT in both Randall-Selitto (mechanical hyperalgesia) and von-Frey hair test (mechanical allodynia). A decrease in the nociceptive threshold was accompanied by significantly increased oxidative stress, nitrite levels and cytokines (tumor necrosis
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factor-α, interleukin-1β and tissue growth factor-β1) both in the serum and sciatic nerves of diabetic rats. Treatment with the E . officinalis aqueous extract (250, 500 and 1000 mg/kg daily) significantly attenuated all the behavioral and biochemical alterations in a dosedependent manner. The major finding of the study is that insulin alone corrected the hyperglycemia and partially reversed the pain response in diabetic rats. However, the combination of insulin with E . officinalis extract not only attenuated the diabetic condition but also reversed neuropathic pain through modulation of oxidative-nitrosative stress in diabetic rats.(17)
E . officinalis contains tannins, saponins, flavanoids, terpenoids and phenols. The tannins include gallic acid, ellagic acid, and pyrogallol.(18) The terpenoids include norsesquiterpenoids, corilagin, geraniin, elaeocarpusin, and prodelphinidins B1 and B2.(18) The phenols and flavonoids in the plant have been described as antiinflammatory agents.
Ginkgo Biloba Ginkgo biloba extract EGb 761 is an extract from Ginkgo biloba tree leaves. It is known for its beneficial effect on brain functioning.(19) It increases the walking distance in patients with intermittent claudication and decreases gastrointestinal injury caused by stress. It also has a protective effect against hepatic injury caused by CCl4 in rats.(19) EGb 761 is composed of 24% flavone glycosides and 6% terpene lactones. The main components of the flavones glycosides are quercetin, kaempferol, and isorhamnetin.(20) The main components of the terpene lactones are ginkgolides A, B, and C and bilobalide.(20) Kim, et al(19) investigated the EGb 761, on the mechanical and cold allodynia in a rat model of neuropathic pain. EGb 761was administered at a dose of 50, 100, 150, and 200 mg/kg. Mechanical and cold allodynia were observed at preadministration and at 15, 30, 60, 90, 120, 150, and 180 min after intraperitoneal drug administration. Mechanical allodynia was quantified by measuring the PWT to stimuli with von Frey filaments of 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 15.0, and 26.0 g. Cold allodynia was quantified by measuring the frequency of foot lift with applying 100% acetone.(20) Intraperitoneal administration of G . biloba extract, EGb 761, attenuated the mechanical and cold allodynia displayed by spinal nerve-ligated rats. But sedation and motor disturbance were observed at the highest doses. This suggests that G .
biloba extract, EGb 761 may exert an analgesic effect in neuropathic pain patients.(19)
Nigella Sativa The black seed, Nigella sativa L. (NS), a member of the family of Ranunculaceae, contains more than 30% fixed oil and 0.4%-0.45% volatile oil. The volatile oil contains 18.4%–24% thymoquinone (TQ) and 46% monoterpenes such as p-cymene and α-piene. Clinical and animal studies have shown that an extract of the black seeds has many therapeutic effects such as immunomodilative, antibacterial, hypotensive, hepatoprotective and antidiabetic effects.(21) Kanter(21) investigated the possible beneficial effects of NS and TQ on histopathological changes of sciatic nerves in streptozotocin (STZ)-induced diabetic rats. The rats in NS and TQ treated groups were given NS (400 mg/kg) and TQ (50 mg/kg) once a day orally by using intragastric intubation for 12 weeks starting 2 days after STZ injection. Both NS and TQ caused a sharp decrease in serum glucose (P
