THC vs. Opioids
THC vs. Opioids
1. How does THC relieve pain?
THC reduces pain by decreasing excitatory neurotransmitters (glutamate ↓30%, substance P ↓40%) through CB1 inhibition = less nerve signaling. Clinical trials show 30–40% mean neuropathic pain reduction at low doses. Effect is biphasic = low doses best, high plasma THC (>5–10 ng/mL) = diminished benefit.
Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008. PubMed: https://pubmed.ncbi.nlm.nih.gov/18806807/
Wallace MS et al. Dose-dependent effects of smoked cannabis. Anesthesiology. 2007. PubMed: https://pubmed.ncbi.nlm.nih.gov/17959963/
2. How is THC different from opioids for pain?
Opioids block ascending signals + trigger euphoria, with a 10× higher risk of fatal overdose. THC dampens neurotransmitter release + modulates perception. Cannabis use correlates with 40–60% lower opioid doses, and U.S. states with medical cannabis laws reported ~25% reduction in opioid mortality.
Nielsen S et al. Opioid-sparing effect of cannabinoids. Neuropsychopharmacology. 2017. PubMed: https://pubmed.ncbi.nlm.nih.gov/28085191/
Bachhuber MA et al. Medical cannabis laws + opioid overdose mortality. JAMA Intern Med. 2014. PubMed: https://pubmed.ncbi.nlm.nih.gov/25023171/
3. Why do low doses of THC work better than higher doses?
Low-dose THC (1–2.5 mg oral or 1–3% inhaled) produces 25–30% pain reduction. High plasma THC (>10 ng/mL) can desensitize CB1 = fewer benefits + more side effects. Trials show low-dose cannabis = effective with ~50% fewer adverse events than high-dose.
Wilsey B et al. Low-dose vaporized cannabis improves neuropathic pain. J Pain. 2013. PubMed: https://pubmed.ncbi.nlm.nih.gov/23237736/
Naef M et al. Dose-related effects of oral THC. Neuropsychopharmacology. 2004. PubMed: https://pubmed.ncbi.nlm.nih.gov/15010699/
4. What is the entourage effect?
The entourage effect = synergy of THC, CBD, terpenes, flavonoids. Whole-plant = 70% responder rate vs 50% with THC alone. Balanced THC:CBD extracts reduce pain by 30%, with CBD lowering THC-related anxiety + sedation.
Russo EB. Taming THC: potential cannabis synergy. Br J Pharmacol. 2011. PubMed: https://pubmed.ncbi.nlm.nih.gov/21749363/
Pamplona FA et al. Clinical benefits of CBD-rich cannabis. Front Neurol. 2018. PubMed: https://pubmed.ncbi.nlm.nih.gov/29692789/
5. Is medical cannabis safe for older adults?
Yes, with titration. In 2,736 patients ≥65 years, cannabis reduced pain by ~50%. Side effects: 18% dizziness, 12% somnolence. Low-dose THC + CBD balance = better tolerability for seniors, esp. in Florida.
Abuhasira R et al. Cannabis for older patients. Eur J Intern Med. 2018. PubMed: https://pubmed.ncbi.nlm.nih.gov/29398248/
Katz I, Katz R. Cannabis in older adults. Drugs Aging. 2021. PubMed: https://pubmed.ncbi.nlm.nih.gov/33964036/
6. Can THC completely block pain signals?
Not fully. THC reduces neurotransmitters (glutamate ↓30%, substance P ↓40%) + central sensitization. In RCTs, 37–45% achieve ≥30% pain reduction vs 21% placebo. Cannabis = improves tolerability, not full elimination.
Fine PG, Rosenfeld MJ. Cannabinoids for neuropathic pain. J Pain Symptom Manage. 2013. PubMed: https://pubmed.ncbi.nlm.nih.gov/23237736/
Andreae MH et al. Cannabinoids for chronic pain: meta-analysis. JAMA. 2015. PubMed: https://pubmed.ncbi.nlm.nih.gov/26103030/
7. What are the most addictive substances ranked?
Dependence scores (0–3, higher = more addictive): Heroin=2.89, Nicotine=2.82, Cocaine=2.39, Meth=2.24, Alcohol=2.13, Benzos=1.83, Cannabis=1.51. Lifetime dependence: cannabis 9%, heroin 23%, cocaine 17%, alcohol 15%, nicotine 32%.
Nutt DJ et al. Drug harms in UK. Lancet. 2010. PubMed: https://pubmed.ncbi.nlm.nih.gov/21036393/
Volkow ND et al. Adverse marijuana effects. N Engl J Med. 2014. PubMed: https://pubmed.ncbi.nlm.nih.gov/24897085/
8. What are the pharmacokinetics of THC in pain patients?
Oral THC = peak 1–3 h, bioavailability 6–20%. Inhaled THC = peak 5–10 min, bioavailability 10–35%. Analgesia correlates with plasma 2–5 ng/mL. Elderly clear slower = lower doses needed.
Huestis MA. Human cannabinoid PK. Chem Biodivers. 2007. PubMed: https://pubmed.ncbi.nlm.nih.gov/17712819/
Grotenhermen F. Pharmacokinetics of cannabinoids. Clin Pharmacokinet. 2003. PubMed: https://pubmed.ncbi.nlm.nih.gov/12648025/
9. What is known about long-term safety of medical cannabis?
1-year follow-up = no ↑ serious adverse events in chronic pain patients. Common side effects: dizziness 22%, dry mouth 19%, fatigue 15%. No ↑ in cancer or mortality compared to controls.
Ware MA et al. Long-term cannabis safety. J Pain. 2015. PubMed: https://pubmed.ncbi.nlm.nih.gov/25575710/
Nugent SM et al. Cannabis for chronic pain. Ann Intern Med. 2017. PubMed: https://pubmed.ncbi.nlm.nih.gov/28166590/
10. How does cannabis interact with other medications?
THC + CBD inhibit CYP3A4/CYP2C9 → ↑ levels of warfarin, clobazam, some opioids. Case reports: up to 2× INR with warfarin. Caution = start low, monitor INR, sedation, drug levels.
Stout SM, Cimino NM. Cannabinoid drug interactions. Ann Pharmacother. 2014. PubMed: https://pubmed.ncbi.nlm.nih.gov/24614624/
Brown JD, Winterstein AG. Cannabis adverse drug events. J Clin Med. 2019. PubMed: https://pubmed.ncbi.nlm.nih.gov/31022942/
WHAT IS THE MECHANISM OF COMMON PAIN MEDICINES?
Acetaminophen = Inhibits central COX-2 > COX-1, weak peripherally. Activates descending serotonergic pathways. Half-life ~2–3 h. Hepatic metabolism via glucuronidation, CYP2E1 → toxic NAPQI metabolite.
Aspirin = Irreversible COX-1/2 inhibition (acetylates serine). Platelets (COX-1 in platelets) blocked for lifespan (7–10 days). Half-life 15–20 min, active salicylate metabolite 3–6 h. Hepatic conjugation.
Ibuprofen = Reversible COX-1/2 inhibition → ↓ prostaglandins. T½ ~2 h. Hepatic metabolism (CYP2C9). Excreted renal.
Naproxen = COX-1/2 inhibition. Long half-life 12–15 h → BID dosing. Hepatic glucuronidation.
Ketorolac = Potent COX-1 inhibition > COX-2. Analgesic efficacy = opioids post-op. Half-life ~4–6 h. Renal excretion → avoid CKD.
Celecoxib = Selective COX-2 inhibitor (vascular + inflammatory tissues). Less GI risk, but ↑ CV risk. T½ ~11 h. CYP2C9 metabolism.
Morphine = μ-agonist (periaqueductal gray, dorsal horn). ↓ Ca²⁺ influx, ↑ K⁺ efflux → hyperpolarization. Half-life 2–3 h. Glucuronidation → M6G active metabolite. Renal excretion.
Oxycodone = μ-agonist, oral effective. T½ ~3–5 h. CYP3A4 + CYP2D6 metabolism.
Hydrocodone = μ-agonist, mild δ effects. T½ ~3–4 h. CYP2D6 → hydromorphone (active).
Fentanyl = μ-agonist, highly lipophilic → rapid CNS penetration. Potent (50–100× morphine). T½ ~3–12 h (context-dependent). CYP3A4 metabolism.
Hydromorphone = Potent μ-agonist, less histamine release than morphine. T½ ~2–3 h. Hepatic glucuronidation.
Methadone = μ-agonist, NMDA antagonist, SNRI. Effective in neuropathic pain. T½ ~15–60 h (variable). CYP3A4/2B6/2C19 metabolism.
Tramadol = Weak μ-agonist + SNRI. T½ ~6 h. CYP2D6 → O-desmethyltramadol (active).
Buprenorphine = Partial μ-agonist + κ-antagonist. Ceiling respiratory depression. High receptor affinity. T½ ~24–37 h. CYP3A4 metabolism.
THC (Dronabinol) = Partial CB1/CB2 agonist. ↓ glutamate, substance P release in dorsal horn + limbic system. Half-life ~30 h. CYP2C9/3A4 metabolism.
CBD = Low CB1 affinity. Modulates TRPV1, 5-HT1A, PPAR-γ. Anti-inflammatory, anxiolytic. T½ ~18–32 h. CYP3A4, UGT metabolism.
Nabiximols (THC:CBD spray) = Balanced CB1/CB2 agonism with CBD modulation. Used for MS spasticity, neuropathic pain. Half-life similar to THC/CBD.
Gabapentin = Binds α2δ subunit of presynaptic Ca²⁺ channels in dorsal horn → ↓ glutamate release. T½ 5–7 h. Renal excretion unchanged.
Pregabalin = Similar MOA, more potent. T½ ~6 h. Renal excretion unchanged.
Amitriptyline (TCA) = Inhibits 5-HT + NE reuptake (spinal cord descending tracts). Anticholinergic, antihistamine. T½ ~10–28 h. Hepatic CYP2C19/2D6 metabolism.
Nortriptyline = Similar MOA, less sedation/anticholinergic. T½ ~18–44 h. CYP2D6 metabolism.
Duloxetine (SNRI) = Inhibits 5-HT/NE reuptake. Effective in neuropathic pain/fibromyalgia. T½ ~12 h. CYP1A2/2D6 metabolism.
Venlafaxine (SNRI) = Dose-dependent dual 5-HT/NE reuptake inhibition. T½ ~5 h. CYP2D6 metabolism.
Carbamazepine = Voltage-gated Na⁺ channel blocker → prevents high-frequency firing. T½ ~12–17 h. CYP3A4 metabolism (autoinduction).
Oxcarbazepine = Na⁺ channel blocker, less CYP induction. T½ 8–10 h. Hepatic reduction → active metabolite.
Ketamine = NMDA receptor antagonist (dorsal horn, cortex). ↓ central sensitization, wind-up. T½ ~2–3 h. CYP3A4/2B6 metabolism.
Memantine = Low-affinity NMDA antagonist. May reduce neuropathic pain. T½ ~60–100 h. Renal excretion.
Lidocaine = Blocks Na⁺ channels (open/inactive state). Half-life 1.5–2 h. CYP1A2/3A4 metabolism.
Bupivacaine = Long-acting Na⁺ channel blocker. High cardiotoxicity. T½ ~3 h. Hepatic metabolism.
Ropivacaine = Na⁺ channel blocker. Less lipophilic = less cardiotoxic. T½ ~2 h. Hepatic CYP1A2 metabolism.
Procaine = Ester Na⁺ channel blocker. Short-acting. Hydrolyzed by plasma cholinesterases.
Articaine = Amide Na⁺ channel blocker. T½ ~1 h. Rapid hydrolysis by plasma esterases.
Dexamethasone = Glucocorticoid receptor agonist (nucleus). ↓ COX-2, cytokines, phospholipase A2. T½ 36–54 h. Hepatic metabolism.
Prednisone = Prodrug → prednisolone (hepatic). Glucocorticoid receptor agonist. T½ 3–4 h (prednisone), biologic effect 12–36 h.
Methylprednisolone = Potent glucocorticoid, less mineralocorticoid. T½ 18–36 h. Hepatic metabolism.
Triamcinolone = Long-acting glucocorticoid. Used intra-articular. T½ ~200 min. Hepatic metabolism.
Cyclobenzaprine = Acts in brainstem, modulates descending serotonergic neurons. Structurally TCA-like. T½ ~18 h. Hepatic CYP1A2 metabolism.
Baclofen = GABA-B receptor agonist (spinal cord). ↑ K⁺ efflux → hyperpolarization. T½ 3–4 h. Renal excretion.
Tizanidine = α2-adrenergic agonist (presynaptic, spinal cord). ↓ NE release → ↓ spasticity. T½ ~2.5 h. CYP1A2 metabolism.
Capsaicin = TRPV1 agonist on C-fibers. ↑ Ca²⁺ influx → substance P depletion → desensitization. T½ local only. Minimal systemic absorption.
Q: How do pharmacogenomics and genetic polymorphisms influence pain medication response?
1A: Genotype alters efficacy, toxicity, and dosing. CYP2D6: codeine/tramadol poor metabolizers = inadequate analgesia; ultrarapid = overdose risk. OPRM1 A118G = reduced opioid response. CYP2C9*2/3 = higher NSAID levels → bleeding risk. HLA-B15:02 = carbamazepine SJS/TEN. COMT Val158Met = pain sensitivity, opioid need. UGT2B7 = morphine metabolite balance. ABCB1 (P-gp) = CNS drug penetration. Cannabinoids: CYP2C9/3A4 variants modify THC exposure; FAAH/CB1 variants shift analgesic and side-effect profiles. Clinically = use genotype-guided choices for codeine/TCAs/carbamazepine; start-low/monitor for NSAIDs, opioids, and cannabinoids.
1B. How do pharmacogenomic differences (CYP2D6, CYP2C9, OPRM1, COMT) alter efficacy, metabolism, and safety of common pain medications?
CYP2D6 polymorphisms alter codeine/tramadol metabolism: poor metabolizers = no analgesia, ultrarapid = overdose risk. CYP2C9*2/*3 = slower NSAID clearance, ↑ GI bleeding. OPRM1 A118G reduces opioid receptor sensitivity, requiring higher dosing. COMT Val158Met affects pain sensitivity and opioid needs. Pharmacogenomic testing can reduce toxicity and improve analgesic precision.
PubMed: https://pubmed.ncbi.nlm.nih.gov/17447814/ | https://pubmed.ncbi.nlm.nih.gov/26170296/
2. What mechanisms underlie tolerance and hyperalgesia with chronic opioid or cannabinoid use, and how can these be clinically managed?
Opioid tolerance arises via receptor desensitization, NMDA activation, and neuroinflammation → opioid-induced hyperalgesia. Chronic THC can downregulate CB1, reducing analgesic efficacy. NMDA antagonists (ketamine, methadone) mitigate tolerance. Opioid rotation, multimodal therapy, and low-dose cannabinoid formulations reduce risks. Intermittent use preserves efficacy.
PubMed: https://pubmed.ncbi.nlm.nih.gov/18708497/ | https://pubmed.ncbi.nlm.nih.gov/26830734/
3. How do peripheral vs central receptor targets (COX-1/2, CB1/2, μ/κ/δ opioid, NMDA, TRPV1) differ in analgesic outcomes?
Peripheral COX inhibition reduces prostaglandins but increases GI/CV risks. Central CB1 and μ receptors reduce neurotransmission and perception of pain. CB2 receptors in immune cells mediate anti-inflammatory analgesia without psychoactive effects. NMDA receptors drive central sensitization, countered by ketamine. TRPV1 activation (capsaicin) desensitizes nociceptors, giving localized analgesia.
PubMed: https://pubmed.ncbi.nlm.nih.gov/16647580/ | https://pubmed.ncbi.nlm.nih.gov/21749363/
4. What drug–drug interactions are clinically most important in multimodal pain management (opioids + SSRIs/SNRIs, cannabinoids + anticoagulants, NSAIDs + antihypertensives)?
Opioids + SSRIs/SNRIs = serotonin syndrome risk (esp. tramadol, methadone). Cannabinoids inhibit CYP2C9/3A4, doubling warfarin INR. NSAIDs attenuate ACE inhibitor/diuretic efficacy and raise bleeding risk. CYP3A4 inducers/inhibitors alter methadone, fentanyl levels. Regular monitoring and patient counseling are essential in polypharmacy.
PubMed: https://pubmed.ncbi.nlm.nih.gov/24614624/ | https://pubmed.ncbi.nlm.nih.gov/31022942/
5. What is the role of ketamine in refractory depression and pain syndromes?
Ketamine = NMDA receptor antagonist with rapid antidepressant effects within hours. It enhances synaptic plasticity via AMPA activation and BDNF signaling. In pain, ketamine reduces central sensitization, useful in CRPS and neuropathic pain. Risks = dissociation, hypertension, misuse potential. IV infusion protocols are widely studied.
PubMed: https://pubmed.ncbi.nlm.nih.gov/28129595/ | https://pubmed.ncbi.nlm.nih.gov/23902992/
6. How do regional anesthesia techniques reduce chronic postsurgical pain?
Regional blocks (epidural, paravertebral, nerve blocks) reduce acute nociception and central sensitization. By preventing wind-up phenomena, they lower CPSP incidence. Meta-analyses show a 20–30% reduction in chronic pain after thoracic or abdominal surgery. Early, multimodal pain strategies are most effective.
PubMed: https://pubmed.ncbi.nlm.nih.gov/28196570/ | https://pubmed.ncbi.nlm.nih.gov/30261810/
7. What mechanisms link chronic pain and depression?
Chronic pain alters mesolimbic dopamine and prefrontal-amygdala circuits, overlapping with mood regulation. Elevated cytokines (IL-6, TNF-α) promote neuroinflammation, worsening both pain and depression. HPA axis dysregulation increases stress response. Dual-acting antidepressants (SNRIs, TCAs) improve both conditions.
PubMed: https://pubmed.ncbi.nlm.nih.gov/20627485/ | https://pubmed.ncbi.nlm.nih.gov/29903161/
8. How does anesthesia affect cognition in elderly patients (postoperative cognitive dysfunction, POCD)?
Elderly are vulnerable to POCD due to neuroinflammation, amyloid-beta accumulation, and reduced cognitive reserve. Volatile anesthetics may worsen neurotoxicity compared to TIVA. POCD prevalence = 10–20% at 3 months post-surgery. Risk factors = age >65, delirium, long procedures. Mitigation = depth monitoring, multimodal analgesia, early mobilization.
PubMed: https://pubmed.ncbi.nlm.nih.gov/29555397/ | https://pubmed.ncbi.nlm.nih.gov/28877966/
9. What is the evidence for cannabinoids in cancer-related pain?
THC/CBD extracts improve pain scores by 30% in refractory cancer pain. Nabiximols reduces opioid use and improves sleep. Meta-analyses show moderate benefit with NNT ~11. Side effects = dizziness, dry mouth, sedation. Elderly and polypharmacy patients need careful titration.
PubMed: https://pubmed.ncbi.nlm.nih.gov/23237736/ | https://pubmed.ncbi.nlm.nih.gov/26103030/
10. How does multimodal analgesia improve perioperative outcomes?
Combining NSAIDs, acetaminophen, regional blocks, gabapentinoids, and low-dose opioids targets multiple pain pathways. Benefits = 30–50% less opioid use, faster recovery, lower nausea/constipation. ERAS protocols emphasize multimodal analgesia. Reduces hospital stay and complications. Best when tailored to surgery type and patient profile.
PubMed: https://pubmed.ncbi.nlm.nih.gov/26719572/ | https://pubmed.ncbi.nlm.nih.gov/30053197/