Curcumin in turmeric: Basic and clinical evidence for a potential role in analgesia
- J. Eke-Okoro PharmD1 | R. B. Raffa PhD1,2 | J. V. Pergolizzi Jr MD3 | F. Breve PharmD4 | R. Taylor Jr. PhD3 | For the NEMA Research Group
What is known and objective:
Current analgesic pharmacotherapy—opioids, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen (paracetamol) and related drugs—is effective for acute pain, but their use is limited by adverse effects on the renal, hepatic, cardiovascular or gastrointestinal systems, or they have potential for abuse. Therefore, alternative options are desired. Compounds used in traditional medicine might offer such alternatives, but the evidence must be based on pharmacologic properties and on clinical trial data. This review summarizes the evidence for one of these: the analgesic properties of turmeric and other curcumins.
Methods: The PubMed database and other sources were searched using keywords related to turmeric, curcumin, antinociception and analgesia. Primary sources and reviews of preclinical and clinical studies were identified, assessed and summarized. Bibliographies within these sources provided additional information.
Results: Turmeric has consistently been demonstrated to produce analgesic and anti-inflammatory effects in animal models and in clinical trials, and appears to have less serious adverse effects than many current analgesics.
What is new, and conclusions: Turmeric (curcumin) appears to be a possible candidate for consideration for use as a stand-alone analgesic, or in analgesic combinations as part of opioid-, NSAID- or paracetamol (acetaminophen)-sparing strategies.
1 | WHAT IS KNOWN AND OBJECTIVE
Pain and inflammatory conditions are very often the main direct or underlying reasons why people seek medical care, and such conditions become even more common with ageing. Unfortunately, although many of the currently available opioid and non-opioid pharmacotherapeutic options, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen (paracetamol) and others, are effective, they have use-limiting adverse effects on gastrointestinal, kidney, liver or cardiovascular systems. Opioids have the additional problem of misuse and abuse potential. Thus, more analgesic options are desired.
Some of the oldest medical systems (e.g., Ayurvedic medicine, also Ayurveda) list or use turmeric for the management of musculoskeletal type pain, but many Western healthcare providers are unfamiliar with the extensive evidence base for the use of turmeric, and chemically related substances for this purpose. This review examines the evidence for the use of turmeric for the management of pain, specifically for treating the pain associated with gastrointestinal and musculoskeletal conditions.[/caption]
2 | METHODS
A MEDLINE/PubMed search was conducted for the period 1946-2018 using specific search terms such as turmeric (~3000 hits), curcumin (~9400 hits), and analgesia or antinociception (~66 500 hits). The Boolean search of turmeric OR curcumin AND analgesia OR antinociception yielded 16 hits. Additional searches sought general information from reviews on pain (eg pathways and types), analgesics [opioids, NSAIDs, acetaminophen (paracetamol), etc.], and turmeric and curcumin (eg composition, pharmacokinetics, formulations, mechanism of action (pharmacodynamics) and toxicology-safety-adverse effects. The searches included articles written on basic science, preclinical in vitro and in vivo testing, and clinical trials. References within identified articles led to further sources (in print or available on the Internet). Each English-language article (~100) was assessed and included if applicable to the topic.
3 | RESULTS
Turmeric is obtained from the herbaceous perennial plant Curcuma longa, which is a member of the ginger family. It is native to southwest India and has many applications—medicinal, religious and culinary (e.g., in curry powder). Turmeric is often referred to as the “golden spice” and is used for a wide range of ailments. Importantly, it has reportedly minimal adverse effects. Its use is now widespread in the world, where it is also used as a dye (yellow-orange) and to create temporary designs on the skin, in the perfume industry for its mild aroma, and as a skin softener in soaps and lotions.
3.1 | Composition of turmeric
Turmeric contains several classes of biologically active substances, for example curcuminoids (linear diarylheptanoids such as curcumin or derivatives of curcumin) including curcumin (diferuloyl methane, demethoxycurcumin and bisdemothoxy curcumin), plus other phyto-chemicals, volatile oils (eg, turmerone, atlantone, zingiberene), sugars, proteins and resins. Curcumin (diferuloylmethane) comprises approximately 2%-5% of the total composition of turmeric, is the component that imbues it with its vibrant deep yellow color and is believed to be the major active therapeutic agent.
3.2 | Pharmacokinetics: ADME (absorption, distribution, metabolism and elimination)
In animal studies, curcumin shows only limited systemic bioavailability following oral administration. This is due to poor absorption and rapid metabolism and excretion. For example, a peak plasma concentration of only 1.8 mg/mL of curcumin was measured in rats when a 500 mg/kg oral dose was administered, and there was almost complete plasma clearance by 1 hour following the intravenous administration of 40 mg/kg. Various rodent studies support the notion that the limited bioavailability of curcumin is due to its rapid metabolism, which results in either Phase II conjugation of curcumin to curcumin glucuronide and curcumin sulphate or Phase I enzymatic reduction in curcumin to dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin and hexahydrocurcuminol.
There are only a few studies that have evaluated the pharmacokinetic properties of curcumin comprehensively in humans. A study that compared the metabolism of curcumin in humans and rats reported that curcumin is extensively metabolized to its sulphate and glucuronide conjugates and reduced to hexahyrocurcumin and tetraydrocurcumin in the intestinal lumen in both species, but the gastrointestinal metabolism of curcumin conjugates is more extensive in humans than in rats. Some human studies, like the rodent studies, suggest poor gastrointestinal absorption and a consequently poor systemic bioavailability which is more evident at lower doses. In one such study, subjects were given an initial 500 mg daily dose of curcumin which over time was increased to a maximum dose of 8000 mg daily. The lowest serum levels of curcumin, almost undetectable in some cases, were observed in subjects receiving 500-2000 mg daily. A mean serum curcumin level of 1.77 ± 1.87 μm was observed in subjects who received the maximum dose. For subjects receiving daily doses of 4000 mg and 6000 mg, serum concentrations of curcumin were 0.51 ± 0.11 μm and 0.63 ± 0.06 μm, respectively. A study of 12 subjects given either 10 g (n = 6) or 12 g (n = 6) curcumin orally suggests that curcumin has better oral absorption at higher doses than at lower doses and that the levels in plasma are detected as curcumin sulphate and curcumin glucuronide, with curcumin glucuronide being predominant.
It has been suggested that the bioavailability of curcumin can be improved by addition of adjuvants that block its degradative metabolic pathways. For example, when curcumin was combined with hydrophilic carriers, cellulosic derivatives and natural antioxidants, serum concentration of curcumin was significantly increased in 12 healthy volunteers, but when the curcumin was administered alone, serum concentration of curcumin was barely detectable in humans. When piperine (which is an inhibitor of glucuronidation in the liver and the intestine) was co-administered with curcumin to humans, there was a statistically significant increase in the serum concentration of curcumin at 0.75 hour post-administration
(P < .01).
3.3 | Pharmacodynamics: mechanism(s) of action
One of the major pharmacologic effects of curcumin is pain relief. Pain can be alleviated by drugs such as NSAIDs and corticosteroids that provide anti-inflammatory benefits by inhibiting the cyclooxygenase (COX) isozymes COX-1 (constitutively active) and COX-2 (inducible). Unfortunately, long-term use of medications that block the COX-1 isozyme can lead to severe gastrointestinal irritation and to ulcers, as well as kidney dysfunction, and long-term use of medications that block the COX-2 isozyme can lead to severe cardiovascular-related morbidity and mortality. Unlike conventional analgesics, curcumin selectively inhibits lipoxygenase, phospholipase A2 and COX-2, but not COX-1, thereby resulting in anti-inflammatory and analgesic benefits without side effects associated with non-selective analgesics.
3.4 | Analgesic/and anti-inflammatory effects of turmeric
3.4.1 | Preclinical studies
In a study by Neha et al the antinociceptive and antipyretic activities of rhizome extracts of C. longa were determined. Thirty-six rats of both sexes (150-200g) were divided into six groups, and either saline (as the control) or aqueous or alcoholic extracts of turmeric were administered to each of the groups for 7 days. Analgin (metamizole sodium) was used to test for analgesic activity in the tail-immersion method as described by Gosh, and paracetamol was used to screen for antipyretic activity using the method of Bhalla et al The analgesic efficacy of the aqueous and alcoholic turmeric extracts at 100 and 200 mg/kg single oral dose was comparable to that of analgin. However, no antipyretic effect was observed at the same dose.
Curcumin has been reported to produce an antinociceptive effect in acetic acid-induced abdominal constriction tests, model of visceral nociceptive pain, in mice (eg 10-40mg/kg, i.p. dose-relatedly increased response latency, but not the % inhibition of behavior; and 200 mg/kg p.o. of ethanolic extract produced about 50% inhibition of the response). In rats, 20 and 40 mg/kg, p.o. increased response latency and inhibited response. An antinociceptive effect for curcumin ethanolic extract has been reported for the mouse hot-plate (55°C) test (200 mg/kg p.o. increased response latency). In the absence of behavioral interference, activity in this test suggests the possibility of a central nervous system involvement in the site of antinociceptive action. Further evidence for a possible central nervous system component of mechanism of action is suggested by the report that the spinal (intrathecal) administration of curcumin (ED50 = 511.4 μg) produces an antinociceptive effect in Phase 2 of the formalin (5%) test. It was recently reported that oral poly(lactic-co- glycolic acid) (PLGA-curcumin), which is a polymeric nanoparticle formulation designed to overcome the poor bioavailability of curcumin, was inactive in the mouse (52°C) water tail-withdrawal test.
Insight into curcumin’s antinociceptive mechanism(s) of action can be inferred by curcumin’s ability to inhibit response in the formalin test, particularly the second phase, generally regarded as indicative of an opioid-mediated effect. An interaction with the opioid system is also implied by curcumin’s reported ability to attenuate morphine tolerance and withdrawal (the behavioral manifestation of physical dependence).
4 | WHAT IS NEW AND CONCLUSIONS
Pain is a condition that can significantly impair a person’s quality of life. Unfortunately, despite advances in pain research and medications, the adverse effects often associated with short-and long-term use of available agents is still a cause of concern. Therefore, alternatives are desired.
A better analgesic is one that provides pain relief and improves a patient’s overall quality of life without producing serious adverse effects or the potential for abuse. A number of laboratory studies now suggest that the apparent analgesic properties of curcumin can be attributed to known pain-modulatory mechanisms, and in particular to its ability to reduce inflammation by inhibiting pro-inflammatory mediators: lipoxygenase, cyclooxygenase, leukotrienes, thromboxane, prostaglandins, nitric oxide, collagenase, elastase, hyaluronidase, MCP-1, interferon-inducible protein, tumour necrosis factor and interleukin-1253— all of which are known components of pain-transmitting or pain-attenuating pathways. In clinical trials, turmeric has been reported to be effective in alleviating spontaneous pain and sensitization, and to provide these analgesic benefits while maintaining a favourable safety profile. It thus appears that curcumin should be further studied as a possible addition to the analgesic armamentarium as a stand-alone or adjunct agent.
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