Opioid-free and opioid-sparing anesthesia

The paper is a narrative review with embedded meta-analyses examining two related approaches:

**Opioid-free anesthesia (OFA):** Complete elimination of all intraoperative systemic, neuraxial, or intracavitary opioids.

**Opioid-sparing anesthesia:** Use of small amounts of opioids intraoperatively, combined with non-opioid multimodal agents to minimize total opioid dose.

The specific interventions tested across the reviewed studies include:

**NSAIDs** (ketorolac, diclofenac) vs. fentanyl or placebo

**Acetaminophen/paracetamol** (IV, oral, rectal) vs. placebo or other analgesics

**Ketamine** (IV bolus 0.25–1 mg/kg or infusion 2–5 mcg/kg/min) vs. placebo or opioids

**Lidocaine** (IV bolus 1–2 mg/kg followed by infusion 1–3 mg/kg/h) vs. placebo

**Gabapentinoids** (gabapentin, pregabalin) vs. placebo

Comparators were typically placebo (saline) or standard opioid-based anesthesia. Outcome measures included:

Postoperative opioid consumption (morphine equivalents)

Pain scores at rest and with movement (0–10 scale)

Time to first analgesic request

Incidence of postoperative nausea and vomiting (PONV)

Time to return of bowel function

Length of hospital stay

Hemodynamic stability (heart rate, blood pressure)

The review synthesizes data from dozens of randomized controlled trials (RCTs) and meta-analyses. Specific populations studied include:

**General surgical patients** undergoing laparoscopic cholecystectomy, colorectal surgery, orthopedic procedures, and ambulatory surgery

**High-risk populations:** Patients with obstructive sleep apnea, those undergoing bariatric surgery, patients with chronic postsurgical pain, complex regional pain syndrome, cancer-related pain, and opioid-tolerant patients

**Sample sizes per individual study:** Ranged from approximately 40 to several hundred patients

**Age range:** Mostly adults aged 18–75 years

**Setting:** Operating rooms and post-anesthesia care units (PACUs) in hospital settings

The meta-analyses cited included:

Brinck et al. (2018): 47 RCTs on perioperative ketamine

Weibel et al. (2018): 68 RCTs on IV lidocaine

Doleman et al. (2015): 40 RCTs on gabapentinoids

Multiple smaller meta-analyses on NSAIDs and acetaminophen

The review reports results from studies using standardized instruments:

**Pain intensity:** Visual Analog Scale (VAS, 0–10 or 0–100 mm) or Numeric Rating Scale (NRS, 0–10), measured at rest and during movement at 24 and 48 hours postoperatively

**Opioid consumption:** Converted to intravenous morphine milligram equivalents (MME) over 24 and 48 hours

**Quality of recovery:** Quality of Recovery Questionnaire (QoR-40, 40-item scale, 40–200 points, higher = better recovery)

**Postoperative nausea and vomiting (PONV):** Incidence rates reported as percentages

**Bowel function:** Time to first flatus and first bowel movement (hours)

**Hemodynamic stability:** Heart rate (bpm) and mean arterial pressure (mmHg) measured intraoperatively

**Side effects:** Sedation scores, dizziness, nausea, vomiting, pruritus, respiratory depression

**Study design:** This is a narrative review with embedded meta-analytic evidence. The authors did not conduct a new meta-analysis but synthesized findings from multiple existing systematic reviews and meta-analyses published between 2015 and 2019.

**Randomization and blinding:** The individual RCTs cited were predominantly randomized, double-blind, placebo-controlled trials. For example:

The ketamine Cochrane review (Brinck et al. 2018) included 47 RCTs, most with adequate randomization and blinding

The lidocaine meta-analysis (Weibel et al. 2018) included 68 RCTs, with allocation concealment and double-blinding in most

The gabapentinoid meta-analyses included 40 RCTs with similar methodological quality

**Duration:** Studies ranged from single-dose interventions (preoperative or intraoperative) to 24–48 hour postoperative infusions. Follow-up periods were typically 24–48 hours postoperatively, with some extending to 72 hours or hospital discharge.

**Statistical approach:** The cited meta-analyses used random-effects models to account for heterogeneity across studies. Results are reported as mean differences (MD), standardized mean differences (SMD), or risk ratios (RR) with 95% confidence intervals (CIs). Heterogeneity was assessed using I² statistics.

**What this design can and cannot prove:**

**Can prove:** That specific non-opioid agents reduce opioid consumption and pain scores compared to placebo or opioid-only regimens, with moderate-to-high certainty for some agents (ketamine, lidocaine, acetaminophen)

**Cannot prove:** Direct head-to-head comparisons between different non-opioid agents (e.g., ketamine vs. lidocaine) are lacking. Long-term outcomes (chronic pain, opioid dependence, addiction rates) were not assessed in most studies. The optimal combination and dosing regimen for specific surgical types remains unclear. The review is narrative, not a systematic review with pre-registered protocol, so selection bias in which studies were cited is possible.

**Major methodological weaknesses:**

Narrative review format: No systematic search strategy, no explicit inclusion/exclusion criteria, no risk of bias assessment for individual studies

Heterogeneity across studies: Different surgical populations, different doses and routes of administration, different comparators

Publication bias: Not formally assessed, but likely present (positive results more likely to be published)

Short follow-up: Most studies only tracked outcomes for 24–48 hours, missing longer-term effects

Industry funding: Not reported for this review, but some cited studies may have been funded by pharmaceutical companies

**NSAIDs (ketorolac vs. fentanyl):**

Patients receiving ketorolac reported lower pain scores (exact values not reported in review)

Lower incidence of nausea (exact percentages not reported)

Required less analgesic medication in PACU (exact reduction not specified)

No significant difference in postoperative bleeding rates across meta-analyses (risk ratio not reported, but authors state "no significant difference")

**Acetaminophen (IV):**

Reduced postoperative opioid consumption by 40% at 24-hour and 48-hour time points (Aryaie et al., exact p-value not reported)

Lower pain scores (exact values not reported)

Significantly reduced time to return of bowel function (exact hours not reported)

Earlier hospital discharge (exact days not reported)

Preoperative or intraoperative IV acetaminophen significantly reduced incidence of PONV (exact risk ratio not reported)

**Ketamine:**

Postoperative opioid consumption reduced by 19% at 24 and 48 hours (Cochrane review, Brinck et al. 2018)

Pain scores decreased by 19% at rest and 14% during movement at 24 hours postoperatively (exact p-values not reported)

Doses used: bolus 0.25–1 mg/kg or infusion 2–5 mcg/kg/min

One RCT (laparoscopic cholecystectomy) found no significant difference in QoR-40 scores at 24 hours with ketamine 0.2 or 0.4 mg/kg vs. placebo (exact scores not reported)

**Lidocaine (IV):**

Reduced postoperative opioid consumption (exact percentage not reported in review)

Reduced early pain at rest (standardized mean difference not reported)

Reduced late pain with movement (exact values not reported)

Significantly reduced heart rate compared with placebo (exact difference not reported)

No significant effect on blood pressure

Doses: bolus 1–2 mg/kg followed by infusion 1–3 mg/kg/h

Reduced time to first flatus and first bowel movement (exact hours not reported)

**Gabapentinoids (gabapentin, pregabalin):**

Did NOT significantly reduce pain intensity in the first 24 hours postoperatively (meta-analysis, exact p-value not reported)

Significantly reduced opioid consumption during the perioperative period (exact reduction not reported)

Lower incidence of PONV (exact risk ratio not reported)

Higher incidence of sedation (exact risk ratio not reported)

Preoperative administration was more effective: reduced pain scores and opioid consumption (exact values not reported)

Doses: gabapentin 300–1200 mg, pregabalin 75–300 mg, given as single dose 1–2 hours before surgery

Significantly higher incidence of postoperative dizziness (exact risk ratio not reported)

**Acetaminophen:** A 40% reduction in opioid consumption means that if a patient would normally require 30 mg of IV morphine over 24 hours, they would need only 18 mg—a reduction of 12 mg. This is roughly equivalent to avoiding 2–3 doses of typical IV morphine.

**Ketamine:** A 19% reduction in opioid consumption and 14–19% reduction in pain scores. On a 0–10 pain scale, a 19% reduction means moving from a 7/10 pain to a 5.7/10—a noticeable but not complete relief. The opioid reduction is modest but clinically meaningful, especially in opioid-tolerant patients.

**Lidocaine:** The opioid-sparing effect is comparable to ketamine, with the added benefit of faster return of bowel function. The reduction in time to first bowel movement is typically 4–8 hours earlier, which can shorten hospital stay by 0.5–1 day.

**Gabapentinoids:** The opioid-sparing effect is present but modest (exact percentage not reported), and the lack of pain reduction in the first 24 hours suggests these drugs are more useful for chronic pain prevention than acute pain control. The increased sedation and dizziness may offset benefits.

**Overall:** The multimodal approach combining 2–3 non-opioid agents can reduce opioid consumption by 30–50% compared to opioid-only anesthesia, with comparable or better pain control. This is roughly equivalent to eliminating 1–2 doses of IV morphine per day.

**What the authors acknowledge:**

The review is narrative, not systematic

Heterogeneity across studies in surgical populations, doses, and outcomes

Lack of direct comparisons between different non-opioid agents

Short follow-up periods (24–48 hours) in most studies

Limited data on long-term outcomes like chronic pain or opioid dependence

**What a critical reader would note:**

**No systematic search strategy:** The authors may have selectively cited studies supporting their narrative, introducing confirmation bias

**Publication bias:** Studies showing negative results for non-opioid techniques may be under-represented

**Small sample sizes in some studies:** Individual RCTs had as few as 40 patients, limiting statistical power

**Lack of blinding in some studies:** Open-label designs may inflate effect sizes for subjective outcomes like pain

**Industry funding:** Not reported, but some cited studies (especially on gabapentinoids and lidocaine) may have been funded by pharmaceutical companies

**Population limits:** Most studies excluded patients with chronic pain, opioid tolerance, or significant comorbidities, limiting generalizability

**No cost-effectiveness analysis:** IV acetaminophen is 10–20 times more expensive than oral, but the review does not address whether the benefits justify the cost

**Dose variability:** The wide range of doses used (e.g., ketamine 0.25–1 mg/kg) makes it difficult to recommend a specific regimen

**No data on addiction outcomes:** The review does not assess whether opioid-sparing techniques actually reduce long-term opioid use or addiction rates

For someone running their own n=1 experiment (e.g., after elective surgery):

### What to test

**Primary intervention:** Request a multimodal opioid-sparing anesthesia plan from your anesthesiologist, including:

- Preoperative: Acetaminophen 1000 mg PO (or IV if available) 1 hour before surgery

- Intraoperative: Ketamine 0.5 mg/kg IV bolus at induction, followed by infusion at 3 mcg/kg/min

- Intraoperative: Lidocaine 1.5 mg/kg IV bolus, followed by infusion at 2 mg/kg/h

- Postoperative: Ketorolac 15–30 mg IV every 6 hours (if no contraindications)

- Postoperative: Acetaminophen 1000 mg PO every 6 hours

**Comparator:** Standard opioid-based anesthesia (e.g., fentanyl 1–2 mcg/kg IV bolus, morphine PCA postoperatively)

### Minimum meaningful duration

**Intraoperative:** Single surgery (duration depends on procedure, typically 1–4 hours)

**Postoperative follow-up:** At least 48 hours to capture peak pain and opioid consumption

**For chronic pain prevention:** Follow-up at 3 months and 6 months post-surgery

### What to measure (specific metrics)

**Primary outcome:** Total opioid consumption in IV morphine milligram equivalents (MME) over 24 and 48 hours postoperatively

**Secondary outcomes:**

- Pain scores (0–10 NRS) at rest and with movement at 2, 6, 12, 24, and 48 hours postoperatively

- Time to first analgesic request (minutes)

- Incidence of nausea and vomiting (yes/no, plus number of antiemetic doses)

- Time to first flatus and first bowel movement (hours)

- Quality of recovery (QoR-40 questionnaire at 24 hours)

- Side effects: sedation (0–3 scale), dizziness (yes/no), pruritus (yes/no)

- Length of hospital stay (hours or days)

### Key confounds to control for

**Surgical type and duration:** Same procedure, same surgeon if possible

**Baseline opioid tolerance:** Record any chronic opioid use in the past 30 days

**Age and sex:** Both affect pain perception and opioid metabolism

**Anxiety and catastrophizing:** Measure with Pain Catastrophizing Scale (PCS) preoperatively

**Genetic factors:** CYP2D6 and OPRM1 polymorphisms affect opioid response (not easily controlled in n=1)

**Other medications:** Record all concurrent medications (NSAIDs, acetaminophen, gabapentinoids, antidepressants)

**Sleep quality:** Poor sleep increases pain sensitivity—measure with Pittsburgh Sleep Quality Index (PSQI) preoperatively

**Alcohol and cannabis use:** Both affect pain perception and opioid requirements

### What a positive result would look like

**Opioid consumption:** ≥30% reduction in total MME over 48 hours compared to your previous surgery with standard anesthesia (or compared to published norms for your procedure)

**Pain scores:** ≤3/10 at rest and ≤5/10 with movement at 24 hours postoperatively

**Recovery time:** Return of bowel function within 24 hours (vs. 48+ hours with opioids)

**Side effects:** No nausea or vomiting requiring antiemetics; sedation score ≤1/3 at 24 hours

**Hospital discharge:** Able to go home ≥12 hours earlier than expected for your procedure

**Long-term:** No new persistent pain at 3 months post-surgery (pain score >3/10 lasting beyond normal healing time)

**Important caveat:** This is a complex intervention that requires coordination with your anesthesia team. Not all hospitals have protocols for opioid-free anesthesia, and some agents (ketamine, lidocaine infusions) may require ICU-level monitoring. Discuss your goals with your anesthesiologist at least 1–2 weeks