Pain & Inflammation: Ethnopharmacology of Analgesic Plants

Introduction/Overview

The management of pain and inflammation represents a cornerstone of clinical medicine, with significant global implications for patient morbidity and quality of life. While synthetic pharmaceuticals dominate contemporary therapeutic regimens, a substantial proportion of the world’s population continues to rely on plant-based medicines, either as primary treatment or as complementary agents. Ethnopharmacology, the interdisciplinary study of the medicinal use of plants by indigenous cultures, provides a critical scientific bridge between traditional knowledge and evidence-based medicine. This field systematically investigates biologically active plant constituents, offering insights into novel mechanisms of action and potential lead compounds for drug development. The clinical relevance of this topic is underscored by the ongoing need for effective analgesics with improved safety profiles, particularly in light of the public health challenges associated with opioid misuse and the gastrointestinal and cardiovascular risks of certain non-steroidal anti-inflammatory drugs.

The importance of understanding analgesic plants extends beyond mere academic interest. Many conventional drugs, such as aspirin (from willow bark), morphine (from opium poppy), and paclitaxel (originally from Pacific yew), have direct botanical origins. A comprehensive grasp of plant-derived analgesics equips future clinicians and pharmacists to critically evaluate alternative therapies, counsel patients on potential herb-drug interactions, and appreciate the cultural context of healthcare. Furthermore, the biodiversity of plant secondary metabolites continues to offer promising scaffolds for the development of new analgesic and anti-inflammatory agents with potentially novel targets.

Learning Objectives

• Classify major analgesic and anti-inflammatory plants based on their primary active phytochemical constituents and therapeutic targets.
• Explain the molecular and cellular mechanisms of action for key plant-derived compounds, including their interactions with cyclooxygenase enzymes, opioid receptors, ion channels, and inflammatory mediators.
• Analyze the pharmacokinetic profiles of representative plant extracts and isolated compounds, including considerations for absorption, metabolism, and potential drug interactions.
• Evaluate the clinical evidence supporting the therapeutic use of specific analgesic plants for conditions such as osteoarthritis, neuropathic pain, and headache, while recognizing limitations in the data.
• Identify significant adverse effects, contraindications, and special population considerations associated with commonly used botanical analgesics.

Classification

Analgesic and anti-inflammatory plants can be classified according to multiple schemata, including botanical taxonomy, chemical structure of active constituents, and primary mechanism of pharmacological action. A mechanistic and chemical classification is most pertinent for clinical and pharmacological understanding.

Chemical Classification of Active Constituents

The therapeutic effects of analgesic plants are mediated by diverse classes of secondary metabolites. These chemical families often dictate the mechanism of action, pharmacokinetic behavior, and toxicity profile.

• Phenolic Compounds: This large class includes several subcategories with significant analgesic and anti-inflammatory properties.
  • Salicylates: Found in Salix alba (white willow) and Filipendula ulmaria (meadowsweet). The prototypical compound is salicin, which is metabolized to salicylic acid.
  • Flavonoids: Ubiquitous in plants like Ginkgo biloba and Citrus species. Quercetin and kaempferol are examples known to modulate inflammatory pathways.
  • Curcuminoids: The principal active component of Curcuma longa (turmeric), with curcumin being the most studied.
  • Capsaicinoids: Vanillamides such as capsaicin from Capsicum species (chili peppers), which act on transient receptor potential vanilloid 1 (TRPV1) channels.
• Alkaloids: Nitrogen-containing compounds often with potent pharmacological activity.
  • Isoquinoline Alkaloids: Include morphine and codeine from Papaver somniferum (opium poppy), acting primarily on μ-opioid receptors.
  • Tropane Alkaloids: Such as atropine and scopolamine, which have limited direct analgesia but are used as adjuncts.
  • Indole Alkaloids: Like reserpine, which has historical use but is not a primary analgesic.
  • Purine Alkaloids: Caffeine from Coffea arabica, often used as an adjuvant in analgesic formulations for headache.
• Terpenes and Terpenoids: A vast class built from isoprene units.
  • Monoterpenes: Menthol from Mentha species, activating TRPM8 cold receptors.
  • Sesquiterpene Lactones: Parthenolide from Tanacetum parthenium (feverfew), used in migraine prophylaxis.
  • Diterpenes: Phytocannabinoids like Δ⁹-tetrahydrocannabinol (THC) from Cannabis sativa.
  • Triterpenes: Boswellic acids from Boswellia serrata (frankincense) gum resin.
• Glycosides: Molecules where a sugar moiety is bound to a non-carbohydrate aglycone.
  • Iridoid Glycosides: Aucubin and harpagoside from Harpagophytum procumbens (devil’s claw).
  • Anthraquinone Glycosides: Found in plants like senna; their analgesic effect is typically indirect via treatment of constipation-related discomfort.
• Fatty Acids and Resins: Including the caffeic acid phenethyl ester (CAPE) in propolis, and the complex resin mixtures of Boswellia and Commiphora (myrrh) species.

Mechanism-Based Classification

• Cyclooxygenase (COX) Inhibitors: Plants containing salicylates (willow bark) and certain flavonoids act as non-selective COX-1 and COX-2 inhibitors, analogous to non-steroidal anti-inflammatory drugs (NSAIDs).
• Opioid Receptor Agonists: Plants producing morphine, codeine, and related opium alkaloids are classic examples of μ-opioid receptor agonists.
• Transient Receptor Potential (TRP) Channel Modulators: This category includes capsaicin (TRPV1 agonist/desensitizer) from chili peppers and menthol (TRPM8 agonist) from mint.
• Endocannabinoid System Modulators: Cannabis sativa contains phytocannabinoids like THC (a CB1 and CB2 receptor partial agonist) and cannabidiol (CBD), which has a more complex pharmacology involving multiple receptor systems.
• NF-κB Pathway Inhibitors: Several plant compounds, including curcumin, boswellic acids, and parthenolide, exert anti-inflammatory effects by inhibiting the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling cascade, a master regulator of inflammatory gene expression.
• Leukotriene Synthesis Inhibitors: Boswellic acids from frankincense are noted for their specific inhibition of 5-lipoxygenase (5-LOX), reducing leukotriene production.
• Peripheral Analgesics/Counter-Irritants: Plants producing volatile oils like menthol, camphor, and methyl salicylate (wintergreen) act via topical counter-irritation, producing a cooling or warming sensation that may modulate pain perception.

Mechanism of Action

The pharmacodynamic actions of analgesic plants are multifaceted, often involving simultaneous modulation of multiple inflammatory and nociceptive pathways. This polypharmacology can be advantageous, potentially leading to synergistic effects, but also complicates the prediction of side effects and interactions.

Modulation of Arachidonic Acid Metabolism

A primary mechanism for many anti-inflammatory plants is interference with the cyclooxygenase (COX) pathway. Salicin, the prodrug found in willow bark, is hydrolyzed and oxidized in vivo to yield salicylic acid. Salicylic acid inhibits the activity of both COX-1 and COX-2 isoforms, albeit through a mechanism distinct from most NSAIDs; it acetylates a serine residue (Ser530 in COX-1) and non-competitively blocks the access of arachidonic acid to the active site. This results in reduced synthesis of prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂), key mediators of inflammation, pain, and fever. Other phenolic compounds, such as certain flavonoids, may also exhibit COX inhibitory activity, although their potency is generally lower than that of isolated pharmaceutical agents.

Inhibition of the 5-lipoxygenase (5-LOX) pathway represents another strategic target. Boswellic acids, particularly 3-O-acetyl-11-keto-β-boswellic acid (AKBA) from Boswellia serrata, directly inhibit 5-LOX, the enzyme responsible for converting arachidonic acid to leukotrienes (e.g., LTB₄). Leukotrienes are potent chemotactic agents that promote neutrophil migration and contribute to the pathogenesis of chronic inflammatory conditions like rheumatoid arthritis and asthma. The dual or selective inhibition of these pathways may offer a different side effect profile compared to traditional NSAIDs.

Interaction with Opioid and Cannabinoid Receptors

Opium alkaloids from Papaver somniferum provide the archetypal model for central analgesia. Morphine and its derivatives act as agonists, primarily at the μ-opioid receptor (MOR), with lesser activity at δ (DOR) and κ (KOR) receptors. Activation of MOR, a G_i/o-protein coupled receptor, leads to inhibition of adenylate cyclase, reduced neuronal excitability via opening of potassium channels, and inhibition of voltage-gated calcium channels. The net effect is the suppression of neurotransmitter release (e.g., substance P, glutamate) in the dorsal horn of the spinal cord and modulation of pain perception in supraspinal regions like the periaqueductal gray.

Phytocannabinoids interact with the endocannabinoid system. Δ⁹-Tetrahydrocannabinol (THC) acts as a partial agonist at cannabinoid receptors CB1 (predominantly central) and CB2 (predominantly peripheral on immune cells). CB1 activation mediates psychoactive effects and contributes to analgesia through inhibition of neurotransmitter release. Cannabidiol (CBD) has low affinity for CB1/CB2 but modulates pain through multiple mechanisms, including activation of serotonin 5-HT_1A receptors, agonism at transient receptor potential vanilloid type 1 (TRPV1), and inhibition of adenosine reuptake. The combined effect in whole-plant extracts may involve an “entourage effect,” where multiple compounds modulate the overall pharmacological response.

Action on Ion Channels and Sensory Receptors

Several plant compounds exert analgesic effects via direct action on ion channels involved in nociception. Capsaicin, the pungent principle of chili peppers, is a potent agonist of the TRPV1 receptor, a non-selective cation channel activated by heat, protons, and various ligands. Initial application causes excitation of nociceptive neurons, perceived as burning pain, followed by a lasting desensitization or defunctionalization of the nerve terminal. This desensitization is mediated by calcium influx, mitochondrial dysfunction, and eventual reversible retraction of sensory nerve endings, leading to reduced pain transmission.

Conversely, menthol from mint plants activates TRPM8, a receptor sensitive to cold temperatures. This activation produces a cooling sensation that can interfere with the transmission of pain signals, a phenomenon known as “cold analgesia.” Some evidence suggests menthol may also modulate voltage-gated sodium and calcium channels, further contributing to its local anesthetic-like properties.

Modulation of Inflammatory Transcription Factors and Cytokines

A broad-spectrum anti-inflammatory action is characteristic of compounds like curcumin and parthenolide. Curcumin, from turmeric, has been shown to downregulate the expression of COX-2, inducible nitric oxide synthase (iNOS), and various pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) primarily by inhibiting the activation of NF-κB. It blocks the phosphorylation and subsequent degradation of IκB, the inhibitory protein that sequesters NF-κB in the cytoplasm, thereby preventing its nuclear translocation and DNA binding. Parthenolide, from feverfew, also acts as an NF-κB inhibitor but through a direct covalent modification of the p65 subunit, and it may additionally inhibit the release of serotonin from platelets and polymorphonuclear leukocyte granules, which is relevant to migraine pathophysiology.

Other Mechanisms

Additional mechanisms contribute to the overall analgesic profile of various plants. Harpagoside from devil’s claw may exhibit anti-inflammatory effects independent of COX inhibition, possibly involving nitric oxide pathways. The iridoid glycosides in plants like devil’s claw might also inhibit the expression of matrix metalloproteinases, which are involved in cartilage degradation in osteoarthritis. Caffeine, while not analgesic per se, is frequently combined with analgesics; it may constrict cerebral blood vessels in migraine and enhance the absorption and potency of other analgesics through adenosine receptor antagonism and other mechanisms.

Pharmacokinetics

The pharmacokinetic profiles of plant-derived analgesics vary immensely, from compounds with rapid absorption and short half-lives to those with poor oral bioavailability requiring specialized formulations. The complexity is heightened when considering whole plant extracts, which contain multiple compounds that may influence each other’s absorption and metabolism.

Absorption

Absorption of active constituents is influenced by their chemical nature, formulation, and the presence of other plant materials. Alkaloids like morphine are generally well absorbed from the gastrointestinal tract, with oral bioavailability ranging from 20% to 40% due to significant first-pass metabolism. Salicin from willow bark is a prodrug; it is absorbed in the small intestine and sequentially metabolized by intestinal flora and hepatic enzymes to active salicylic acid, a process that results in a delayed onset of action compared to pharmaceutical aspirin.

Many plant phenolics suffer from poor aqueous solubility and rapid metabolism, limiting systemic exposure. For instance, the oral bioavailability of pure curcumin is notoriously low (<1% in some studies) due to poor absorption, extensive glucuronidation and sulfation in the intestinal mucosa and liver, and rapid systemic elimination. This has led to the development of enhanced formulations using phospholipid complexes, nanoparticles, or co-administration with piperine (from black pepper), which inhibits glucuronidation and can increase bioavailability by up to 20-fold. Similarly, the absorption of boswellic acids may be enhanced when taken with a fatty meal.

Distribution

Distribution is dictated by physicochemical properties such as lipophilicity, plasma protein binding, and molecular size. Highly lipophilic compounds like THC and other cannabinoids have large volumes of distribution (V_d > 100 L/kg), rapidly distributing into adipose tissue and the brain, which accounts for their rapid psychoactive onset. Morphine, being less lipophilic than other opioids, has a lower V_d (≈3-4 L/kg) and crosses the blood-brain barrier less efficiently, a factor in its relative potency when administered via different routes. Salicylic acid is highly bound to plasma albumin (>90%), which can be a site for displacement interactions with other drugs like warfarin.

Metabolism

Hepatic metabolism is a dominant factor in the clearance of most plant-derived compounds, primarily via Phase I (oxidation, reduction, hydrolysis) and Phase II (conjugation) reactions.

• Opium Alkaloids: Morphine undergoes extensive Phase II metabolism, primarily glucuronidation by UGT2B7 to morphine-3-glucuronide (M3G, inactive) and morphine-6-glucuronide (M6G, active and potent). The ratio of these metabolites can influence analgesic response and neuroexcitatory side effects.
• Salicylates: Salicylic acid is metabolized primarily by conjugation with glycine to form salicyluric acid and with glucuronic acid to form phenolic and acyl glucuronides. The metabolic pathways are saturable, leading to non-linear pharmacokinetics where increases in dose result in disproportionate increases in plasma concentration and half-life (t_1/2). At low doses, t_1/2 is 2-3 hours, but can extend to 15-30 hours at high, anti-inflammatory doses.
• Cannabinoids: THC is extensively metabolized by hepatic cytochrome P450 enzymes, primarily CYP2C9 and CYP3A4, to 11-hydroxy-THC (also psychoactive) and further to inactive carboxylic acid metabolites. CBD is metabolized by CYP3A4 and CYP2C19, and it is a potent inhibitor of several CYP isoforms, which underlies many of its drug interactions.
• Curcumin: Undergoes rapid reduction to dihydrocurcumin and tetrahydrocurcumin, followed by conjugation to glucuronide and sulfate esters. These metabolites are generally considered less active than the parent compound.

Excretion

Renal excretion is the primary route of elimination for many plant metabolite conjugates. Morphine glucuronides are excreted renally, necessitating dose adjustment in renal impairment to avoid accumulation of M6G. Salicylic acid and its metabolites are also renally excreted, with the clearance being highly urine pH-dependent; alkalinization of urine can dramatically increase elimination. Biliary excretion and fecal elimination play significant roles for compounds like curcumin and boswellic acids. THC metabolites are excreted primarily in feces (≈65%) and urine (≈20%), with detection times in urine extending for days to weeks after chronic use due to release from adipose tissue stores.

Half-life and Dosing Considerations

Half-lives vary widely: morphine (2-4 hours), salicylic acid (dose-dependent, 2-30 hours), THC in occasional users (1-3 days for complete elimination of metabolites), and curcumin (≈2 hours for parent compound). Dosing of botanical preparations is complicated by variability in plant material potency, which depends on genetics, growing conditions, and processing. Standardized extracts, which guarantee a minimum content of a specific marker compound (e.g., 15% boswellic acids, 1.5% harpagoside), are essential for reproducible clinical effects. Dosing schedules must account for the pharmacokinetic profile; for example, willow bark may require multiple daily doses due to the prodrug nature of salicin, while sustained-release opioid formulations are designed to provide longer-lasting analgesia.

Therapeutic Uses/Clinical Applications

The clinical application of analgesic plants spans from well-established, evidence-supported uses to traditional applications requiring further validation. Their role is often in the management of chronic, non-malignant pain conditions where long-term use of conventional NSAIDs or opioids may be problematic.

Approved Indications and Evidence-Based Uses

Regulatory approval status varies by country. In many European nations, certain botanical extracts are approved as traditional herbal medicines or phytomedicines for specific indications.

• Osteoarthritis and Musculoskeletal Pain: Several botanicals have demonstrated efficacy in randomized controlled trials (RCTs). Harpagophytum procumbens (devil’s claw) extracts standardized for harpagoside have shown significant reduction in pain and improvement in function compared to placebo, with effects comparable to low-dose NSAIDs like rofecoxib or diclofenac. Boswellia serrata extracts have shown benefit in reducing pain and stiffness and improving knee joint function in osteoarthritis, attributed to its anti-inflammatory and potential cartilage-protective effects. Topical capsaicin creams (0.025% to 0.1%) are FDA-approved for postherpetic neuralgia and osteoarthritis pain, acting as a counter-irritant and desensitizing agent.
• Low Back Pain: Devil’s claw and white willow bark extract have been recommended in some clinical guidelines as therapeutic options for non-specific low back pain. A meta-analysis of RCTs concluded that willow bark extract (providing 120-240 mg salicin daily) was superior to placebo for short-term improvement in pain and reduced the use of rescue medication.
• Migraine Prophylaxis: Tanacetum parthenium (feverfew) leaf extracts have been extensively studied for migraine prevention. Regular use may reduce the frequency and severity of migraine attacks, with proposed mechanisms involving inhibition of platelet aggregation, serotonin release, and inflammatory pathways. Butterbur (Petasites hybridus) extract, standardized and processed to remove hepatotoxic pyrrolizidine alkaloids, has also shown efficacy in RCTs, though safety concerns require careful product selection.
• Neuropathic Pain: Topical capsaicin high-concentration patch (8%) is approved for postherpetic neuralgia and neuropathic pain associated with HIV. Its application provides pain relief for up to 12 weeks following a single 60-minute treatment. Cannabis-based medicinal products (e.g., nabiximols, a THC/CBD oromucosal spray) are approved in numerous countries for neuropathic pain in multiple sclerosis and, in some jurisdictions, for cancer pain refractory to optimized opioid therapy.
• Inflammatory Bowel Disease and Rheumatoid Arthritis: While not first-line, curcumin has shown adjunctive benefit in pilot studies for maintaining remission in ulcerative colitis and improving disease activity scores in rheumatoid arthritis, likely due to its broad anti-inflammatory and NF-κB inhibitory properties. Boswellia serrata has also been investigated in these conditions with some positive results.

Common Off-Label and Traditional Uses

Many traditional uses lack robust clinical trial evidence but are prevalent in practice. Turmeric (curcumin) is widely used for general “aches and pains” and as an anti-inflammatory supplement. Arnica (Arnica montana) gel or cream is commonly applied topically for muscle aches, bruises, and swelling, though evidence for efficacy beyond placebo is mixed and oral administration is toxic. Ginger (Zingiber officinale) is used for dysmenorrhea and osteoarthritis, with some clinical data supporting its anti-inflammatory and analgesic effects. Kava (Piper methysticum), while primarily anxiolytic, has muscle relaxant properties that may indirectly benefit pain associated with tension. These uses necessitate careful patient counseling regarding the level of evidence and potential risks.

Adverse Effects

The adverse effect profiles of botanical analgesics are as diverse as their mechanisms. A common misconception of “natural equals safe” is pharmacologically untenable; these agents possess intrinsic biological activity capable of causing significant harm.

Common Side Effects

Side effects are often predictable based on the pharmacodynamic class.

• Gastrointestinal Effects: Willow bark, due to its salicylate content, can cause dyspepsia, nausea, and gastric erosion, though the incidence may be lower than with synthetic NSAIDs due to different formulations and the presence of protective polyphenols. Boswellia may cause mild GI upset, diarrhea, or skin rash. High doses of curcumin can cause diarrhea or gastroesophageal reflux.
• Central Nervous System Effects: Opium-derived medications cause drowsiness, dizziness, confusion, and constipation. Cannabis/THC causes dose-dependent psychoactive effects: euphoria or dysphoria, anxiety, impaired memory and concentration, and motor coordination deficits. Feverfew can cause mouth ulcers and gastrointestinal irritation; a “post-feverfew syndrome” of rebound headache and nervousness may occur upon abrupt discontinuation after chronic use.
• Topical Agents: Capsaicin creams universally cause a transient burning sensation, erythema, and itching at the application site. These effects usually diminish with repeated use as desensitization occurs. Menthol can cause skin irritation or contact dermatitis in sensitive individuals.

Serious/Rare Adverse Reactions

• Hepatotoxicity: This is a significant concern with certain botanicals. Kava has been associated with rare but severe hepatotoxicity, leading to its ban or restriction in several countries. The mechanism is not fully understood but may involve inhibition of cytochrome P450 enzymes, genetic polymorphisms, or the use of inappropriate plant parts or extraction solvents. Comfrey (Symphytum officinale), used topically for sprains, contains hepatotoxic pyrrolizidine alkaloids that can cause veno-occlusive disease if absorbed systemically or taken orally.
• Renal Toxicity: Chronic, high-dose use of willow bark, like other salicylates, carries a risk of interstitial nephritis and papillary necrosis, particularly in volume-depleted states.
• Cardiovascular Effects: Salicylates in high doses can cause sodium and water retention. The cardiovascular safety profile of selective COX-2 inhibitory compounds in plants is less clear than for pharmaceuticals, but theoretical risks exist. Ephedra (ma-huang), sometimes used for pain associated with cold, contains ephedrine alkaloids which are potent sympathomimetics and can cause hypertension, tachycardia, arrhythmias, stroke, and myocardial infarction.
• Respiratory Depression: This is the most serious acute adverse effect of opioid agonists like morphine and codeine, particularly with overdose or in opioid-naïve individuals.
• Psychiatric Effects: Chronic, heavy cannabis use is associated with an increased risk of psychosis in predisposed individuals and can induce or exacerbate anxiety and depressive disorders.
• Allergic Reactions: Plants in the Asteraceae family (e.g., feverfew, arnica, chamomile) can cause allergic reactions, including contact dermatitis and, rarely, anaphylaxis, in individuals sensitive to sesquiterpene lactones.

Black Box Warnings and Major Safety Concerns

While formal FDA black box warnings are typically assigned to specific drug products, the active principles in plants carry analogous risks. Opioid agonists from poppy have black box warnings for addiction, abuse, misuse, life-threatening respiratory depression, and accidental ingestion. The risks of dependence, tolerance, and addiction are paramount. Salicylate-containing plants carry a warning regarding Reye’s syndrome, a rare but severe encephalopathy and liver failure associated with salicylate use in children and adolescents with viral infections. Cannabis-derived products may carry warnings about psychiatric effects, impaired driving, and potential for abuse. The lack of regulatory oversight for many dietary supplements means these warnings are often not communicated to consumers effectively.

Drug Interactions

Botanical analgesics can participate in significant pharmacokinetic and pharmacodynamic interactions, posing risks for treatment failure or toxicity.

Major Pharmacokinetic Interactions

These primarily involve modulation of drug-metabolizing enzymes and transporters.

• Cytochrome P450 Inhibition: Many plant compounds inhibit CYP enzymes. Cannabidiol (CBD) is a potent inhibitor of CYP2C19 and CYP2D6 and a moderate inhibitor of CYP3A4 and CYP2C9. This can increase plasma levels of drugs metabolized by these pathways, such as warfarin (increased INR and bleeding risk), clobazam (increased sedation), and several antidepressants, antipsychotics, and statins. Curcumin and capsaicin may also inhibit various CYP isoforms, though clinical significance is less established.
• Cytochrome P450 Induction: St. John’s wort (Hypericum perforatum), often used for comorbid depression in pain patients, is a potent inducer of CYP3A4 and P-glycoprotein. This can dramatically reduce the plasma concentrations and efficacy of co-administered drugs, including opioids (oxycodone, methadone), anticoagulants, antiepileptics, and many others.
• UGT Enzyme Interactions: Compounds may interfere with glucuronidation. Curcumin and some flavonoids can inhibit UGT enzymes, potentially affecting drugs like morphine (increasing M6G formation) and acetaminophen.
• Protein Binding Displacement: Salicylic acid is highly protein-bound and can displace other drugs like warfarin, methotrexate, and valproic acid from albumin, transiently increasing their free, active fraction and potentiating their effects and toxicity.

Major Pharmacodynamic Interactions

• Additive Sedation/Respiratory Depression: The combination of opioid-containing plants (or synthetic opioids) with other CNS depressants—including alcohol, benzodiazepines, sedative-hypnotics, and cannabis/THC—can lead to profound sedation, respiratory depression, coma, and death.
• Additive Anticoagulation: Plants with antiplatelet or anticoagulant properties (e.g., willow bark/salicylates, garlic, ginkgo, ginger) can potentiate the effects of warfarin, heparin, direct oral anticoagulants (DOACs), and antiplatelet drugs like clopidogrel, increasing the risk of bleeding.
• Additive Serotonergic Effects: Plants like St. John’s wort (which inhibits serotonin reuptake) and possibly cannabis may interact with serotonergic drugs (SSRIs, SNRIs, tramadol, triptans) to increase the risk of serotonin syndrome, characterized by agitation, hyperthermia, autonomic instability, and neuromuscular abnormalities.
• Hypertensive Crisis: Plants containing tyramine (e.g., in some fermented or aged plant products) or sympathomimetic amines (ephedra) can interact with monoamine oxidase inhibitors (MAOIs), leading to a dangerous rise in blood pressure.
• Reduced Efficacy: The anti-inflammatory effect of willow bark may be antagonized by corticosteroids. Furthermore, chronic cannabis use might induce tolerance to opioids, requiring higher doses for equivalent analgesia.

Contraindications

Absolute contraindications are based on the known risks of the active principles.

• Salicylate-containing plants (Willow, Meadowsweet): Contraindicated in children and adolescents with viral infections (Reye’s syndrome risk), in patients with known salicylate allergy, severe renal impairment, active peptic ulcer disease, and in combination with anticoagulants in high-risk patients.
• Opioid-containing plants (Poppy): Contraindicated in significant respiratory depression, acute or severe bronchial asthma, and known gastrointestinal obstruction.
• Cannabis/THC: Contraindicated in individuals with a personal or strong family history of psychosis or schizophrenia. Use with extreme caution in patients with severe cardiovascular disease.
• Kava: Contraindicated in liver disease, during pregnancy/lactation, and with concomitant use of other hepatotoxic substances.
• Feverfew: Contraindicated in individuals with known allergy to plants in the Asteraceae/Compositae family (ragweed, chrysanthemums).
• Topical agents (Capsaicin, Menthol): Contraindicated on broken or irritated skin.

Special Considerations

The use of analgesic plants in specific populations requires careful risk-benefit analysis, often extrapolated from data on their isolated active compounds due to a paucity of specific studies on the botanical preparations themselves.

Pregnancy and Lactation

As a general principle, the use of medicinal plants during pregnancy and breastfeeding should be approached with extreme caution due to limited safety data and potential for teratogenicity or passage into breast milk.

• Pregnancy: Opioid agonists are associated with neonatal opioid withdrawal syndrome (NOWS) when used chronically in the third trimester. Salicylates are generally avoided, especially in the third trimester, due to risks of premature closure of the ductus arteriosus, prolonged gestation and labor, and potential bleeding risks in mother and neonate. Cannabis use is contraindicated due to potential effects on fetal neurodevelopment and low birth weight. Feverfew is contraindicated due to its potential uterotonic activity. Topical capsaicin is considered low risk due to minimal systemic absorption, but should be used only if clearly needed.
• Lactation: Morphine and codeine are excreted in breast milk; codeine in particular is contraindicated due to its metabolism to morphine by ultra-rapid metabolizers, which has led to fatal infant respiratory depression. Salicylates are also excreted and may pose a risk of Reye’s syndrome to the infant. Cannabinoids are lipid-soluble and readily pass into breast milk, potentially affecting infant neurodevelopment. Most other botanicals lack sufficient data, and use is generally not recommended.

Pediatric Considerations

Children are not small adults; their unique physiology, including immature metabolic enzyme systems and different body composition, alters pharmacokinetics and pharmacodynamics. The use of salicylate-containing plants is absolutely contraindicated due to the risk of Reye’s syndrome. Opioids require extreme caution with meticulous dosing based on weight and close monitoring for respiratory depression. There is very limited data on the safety and efficacy of most other botanical analgesics in children. Topical agents like capsaicin may be used in older children under supervision, but the initial burning sensation may not be well tolerated.

Geriatric Considerations

Older adults often have altered pharmacokinetics (reduced hepatic metabolism, decreased renal clearance, altered body composition) and increased pharmacodynamic sensitivity. They are particularly vulnerable to adverse effects.

• Increased CNS Sensitivity: Older patients are more susceptible to the sedative, cognitive-impairing, and delirium-inducing effects of opioids and cannabis.
• Increased Risk of Falls: Sedation, dizziness, and orthostatic hypotension from various botanicals (opioids, cannabis, kava) significantly increase fall and fracture risk.
• Renal and Hepatic Impairment: Age-related decline in renal function necessitates caution with renally excreted compounds like salicylate metabolites and morphine glucuronides. Reduced hepatic blood flow can prolong the half-life of extensively metabolized drugs like THC and curcumin.
• Polypharmacy: The high prevalence of concomitant medication use in the elderly dramatically increases the risk of drug-herb interactions, particularly involving CYP450 enzymes and anticoagulants.

Renal and Hepatic Impairment

Renal Impairment: Dose adjustment or avoidance is critical for compounds or metabolites excreted renally. Morphine-6-glucuronide (M6G) accumulates in renal failure, leading

References

1. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
4. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
6. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.