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Red-Haired People’s Altered Responsiveness to Pain, Analgesics, and Hypnotics: Myth or Fact?—A Narrative Review

5 impactful studies for pain physicians from the past 5 years - based on their influence on clinical practice, guideline development, the introduction of new treatment options

1. CDC Clinical Practice Guideline for Prescribing Opioids for Pain (2022)

This landmark update from the CDC and American Academy of Pain Medicine replaced the 2016 guideline and fundamentally reshaped opioid prescribing across all pain settings.

[1]

Key changes include:

Removal of rigid dose thresholds (e.g., the prior 90 MME ceiling), replacing them with individualized risk-benefit assessments
Expansion of scope to include acute pain and subacute pain, not just chronic pain
Reinforcement that nonopioid pharmacologic therapies (SNRIs, gabapentinoids, NSAIDs) and nonpharmacologic treatments (exercise, CBT, multidisciplinary rehabilitation) are associated with comparable or superior improvements in pain and function versus opioids, with fewer harms
[1]
A pivotal 12-month RCT (SPACE trial) found no difference in function and higher pain intensity with opioid-first versus nonopioid-first stepped therapy for chronic musculoskeletal pain
[1]

This guideline is the single most referenced document in contemporary pain practice and directly influences prescribing, prior authorization, and medicolegal standards.

2. SENZA-PDN Trial — 10-kHz Spinal Cord Stimulation for Painful Diabetic Neuropathy (2021)

This multicenter RCT (n=216) demonstrated that high-frequency (10-kHz) SCS dramatically reduced pain in refractory painful diabetic neuropathy (PDN) compared to conventional medical management alone.

[2]

79% of SCS patients achieved ≥50% pain relief at 3 months vs. only 5% with CMM (P < .001)
Mean VAS pain dropped from 7.6 cm to 1.7 cm at 6 months in the SCS group
Neurological examination improvements were observed in 62% of SCS patients vs. 3% with CMM
24-month follow-up confirmed durability: 90.1% maintained ≥50% pain relief, with 65.7% showing clinically meaningful neurological improvement

3. Basivertebral Nerve (BVN) Ablation Trials for Vertebrogenic Low Back Pain (INTRACEPT/MOTION, 2021)

The INTRACEPT study (open-label RCT, n=140) demonstrated that radiofrequency ablation of the basivertebral nerve produced significant and durable improvements in patients with chronic low back pain associated with Modic changes:

[4]

BVN ablation achieved a 25.7-point ODI reduction and 3.8 cm VAS reduction at 12 months (P < .001 for both)
64% of patients achieved ≥50% pain reduction; 29% were pain-free at 12 months
5-year follow-up from the sham-controlled trial showed sustained results: 75% composite responder rate (≥15-point ODI and ≥2-point VAS improvement), with 34% reporting complete pain resolution
[5]

This body of evidence established vertebrogenic pain as a distinct, treatable phenotype identifiable by Modic changes on MRI, providing pain physicians with a new diagnostic framework and minimally invasive treatment option for a subset of chronic low back pain patients.

4. Percutaneous Peripheral Nerve Stimulation for Acute Postoperative Pain (SPRINT PNS Pilot RCT, 2021)

This sham-controlled, double-masked RCT (n=66) demonstrated that percutaneous PNS dramatically reduced postoperative pain and opioid consumption following ambulatory orthopedic surgery:

[6]

Median opioid consumption in the first 7 days: 5 mg (active) vs. 48 mg (sham) oral morphine equivalents (P < .001)
Average pain scores: 1.1 ± 1.1 (active) vs. 3.1 ± 1.7 (sham) on NRS 0–10 (P < .001)
Benefits were consistent across brachial plexus (rotator cuff repair) and sciatic nerve (foot/ankle surgery) lead locations
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No systemic side effects; leads remained in place for up to 60 days

This study established percutaneous PNS as a viable opioid-sparing neuromodulation strategy for acute pain, distinct from traditional nerve blocks, with the advantage of avoiding motor blockade and not requiring a medication infusion system.

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5. Tanezumab Phase 3 Trials — Anti-NGF Therapy for Osteoarthritis and Chronic Low Back Pain (2019–2022)

The tanezumab program represents the most advanced effort to develop a novel non-opioid analgesic mechanism for chronic musculoskeletal pain. Key findings from phase 3 trials:

In OA of the hip/knee (n=849), tanezumab 5 mg significantly improved WOMAC Pain, Physical Function, and PGA-OA vs. placebo at 24 weeks
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In chronic low back pain (n=1,832), tanezumab 10 mg significantly reduced LBPI vs. placebo at week 16 (treatment difference: −0.40, P = 0.028), with 46.3% achieving ≥50% improvement
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However, rapidly progressive osteoarthritis (RPOA) occurred in 1.4–2.8% of tanezumab-treated patients, and joint replacements were more frequent at higher doses
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A 2026 network meta-analysis confirmed that anti-NGF antibodies provide the greatest pain relief and functional improvement among studied agents, but with significant risks of adjudicated arthropathies (RR 3.84 for tanezumab vs. placebo)
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Despite ultimately not receiving FDA approval due to joint safety concerns, these trials are essential knowledge for pain physicians as they represent the closest a novel non-opioid analgesic class has come to market for musculoskeletal pain and continue to inform the development of next-generation NGF-targeted therapies.

Honorable Mentions

Cohen et al., Lancet 2021 — Comprehensive Lancet Series on chronic pain burden, best practices, and neuromodulation, serving as a definitive reference for the field

5 studies demonstrating opioid reduction with medical cannabis

1. Slawek et al., JAMA Internal Medicine 2025 — MEMO Study (Prospective Cohort, n=204)

This is the most methodologically rigorous prospective study on this topic, using objective pharmacy dispensing data from the New York State Prescription Monitoring Program (PMP).

[1]

Adults with chronic pain on opioids (mean baseline 73.3 MME/day) were followed for 18 months after enrollment in the NYS Medical Cannabis Program
Mean daily MME decreased to 57.4 (a 22% reduction)
Each 30-day supply of medical cannabis dispensed was associated with 3.53 fewer MME/day (95% CI −6.68 to −0.04; P = .03) in marginal structural models
Uniquely accounted for unregulated cannabis use as a time-varying confounder — a major limitation of prior studies
Used pharmacist-reported dispensation in the NYS PMP as the exposure measure, rather than self-report

2. Nguyen et al., JAMA Network Open 2023 — NYS Retrospective Cohort (n=8,165)

The largest patient-level study of medical cannabis and opioid dose reduction, using the same NYS PMP data system but with a much larger retrospective cohort.

[2]

8,165 patients on long-term opioid therapy were stratified by baseline MME (<50, 50–90, ≥90) and divided into exposure (MC >30 days) vs. nonexposure (MC ≤30 days) groups
Opioid reductions were dose-dependent: the highest baseline users (≥90 MME) showed the greatest monthly reduction difference: −9.33 MME/month (95% CI −9.89 to −8.77) vs. nonexposure
By 8 months, the exposure group achieved 48–51% reductions in daily MME across all strata, compared to only 4–14% in the nonexposure group
The dose-response relationship — greater baseline opioid use predicting greater reduction — strengthens the plausibility of a causal association

3. Benedict et al., Pain Physician 2022 — Prospective Clinical Practice Study (n=115)

This single-center prospective study from the Allegheny Health Network uniquely embedded medical cannabis into a structured clinical decision framework where patients chose to continue or discontinue cannabis after a trial period.

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115 chronic pain patients on chronic opioid therapy (mean baseline 49.9 MME/day) trialed medical cannabis
75 patients (65%) chose to continue cannabis and taper opioids; 30 discontinued due to ineffectiveness or side effects
Among those continuing: 67.1% average decrease in daily MME (49.9 → 16.4 MME) at first follow-up
73.3% decrease at second follow-up (49.9 → 13.3 MME; P < .0001)
Compliance monitored via urine drug screens

The magnitude of reduction (>67%) is notably larger than other studies, likely reflecting the self-selected nature of the continuing cohort — patients who did not benefit reverted to their prior opioid regimen.

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4. Bradford et al., JAMA Internal Medicine 2018 — Medicare Part D Population-Level Analysis (2010–2015)

This landmark ecological study examined the association between state medical cannabis laws (MCLs) and opioid prescribing across the entire Medicare Part D population.

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Analyzed all opioid prescriptions filled under Medicare Part D nationwide from 2010–2015
States with any MCL: opioid prescriptions decreased by 2.11 million daily doses per year from an average of 23.08 million
States with medical cannabis dispensaries: opioid prescriptions decreased by 3.74 million daily doses per year
States with home-cultivation-only MCLs: 6.9% reduction in any opioid prescribing
Statistically significant reductions specifically in hydrocodone and morphine prescriptions

A companion study by Wen & Hockenberry (JAMA Internal Medicine 2018) found similar results in the Medicaid population, with adult-use marijuana laws associated with even greater reductions in opioid prescribing than medical-only laws.

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5. Safakish et al., Pain Medicine 2020 — Prospective 12-Month Observational Study (n=751)

The largest prospective observational study of plant-based medical cannabis in a chronic pain clinic population, with 12 months of follow-up.

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751 chronic pain patients initiating medical cannabis were followed monthly for 12 months
Among patients reporting opioid use at baseline, there were significant reductions in oral morphine equivalent doses (P < .0001) over the observation period
Pain severity and interference improved significantly at 1 month and were maintained through 12 months (P < .001)
SF-12 physical and mental health domains improved significantly starting at 3 months (P < .002)
Significant decreases in headaches, fatigue, anxiety, and nausea were also observed

Critical Context: The RCT–Observational Disconnect

A major systematic review by Nielsen et al. (2022) highlights a fundamental tension in this literature: meta-analyses of observational studies found that 39% of patients reported opioid cessation and 85% reported opioid reduction with cannabis, but RCTs have not confirmed opioid-sparing effects.

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Specifically:

Meta-analysis of 4 RCTs in cancer pain: no effect on opioid dose (MD −3.8 mg, 95% CI −10.97 to 3.37)
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3 RCTs of dronabinol in chronic non-cancer pain: no treatment effect
[7]
The Noori et al. (BMJ Open 2021) systematic review similarly concluded that opioid-sparing effects remain uncertain due to very low certainty evidence from RCTs, though observational data showed a WMD of −22.5 MME (95% CI −43.06 to −1.97)
[8]

This disconnect may reflect that RCTs instructed participants to maintain opioid doses (not designed to test tapering), selection bias in observational studies, or that the opioid-sparing effect requires patient-directed dose adjustment over time rather than a pharmacologic interaction.