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Table 1 Study characteristics

From: Zolpidem reduces pain intensity postoperatively: a systematic review and meta-analysis of the effect of hypnotic medicines on post-operative pain intensity

Author Study design Population Intervention Control Outcomes
Bischoff et al. [23] Randomised, placebo-controlled, double-blind trial. 2 arm trial. Sponsorship: none. N = 250 (2 groups of 125); female (%), 57.6%/57.6%. Age 47 years (SD17)/47 years (SD15).
Surgery: 32 different kinds of operation, most frequent being hernias, cholecystectomy, strumectomy, mastectomy, appendectomy and haemorrhoid operations
Benzodiazepine, lormetazepam, oral.
Lormetazepam 2 mg PRN, nightly for 5 nights
Placebo, oral.
Placebo PRN, nightly for 5 nights
1. Pain 100 mm VAS (completed in the am regarding degree of pain experienced during the night, every morning for 5 days)2. Analgesic use
3. Sleep quality 100 mm VAS
-Total sleep duration (patients AX)
-Sleep latency (min)
-Awakenings (no.)
-Feeling of freshness on awakening (100 mm VAS)
Blumenkopf [31] Randomised, placebo-controlled, single-blind trial. 2 arm trial. Sponsorship: none. N = 50 (intervention n = 21, control n = 29);
Female (%), 36% overall. Age, 42 years (SD13) overall
Surgery: spinal surgery.
Benzodiazepine in combination.
Diazepam, oral.
Diazepam 5 mg orally 3 times daily and baclofen 5 mg on day 1, 7.5 mg on day 2 and 10 mg on day 3
Access to promethazine hydrochloride 25 mg, plus meperidine hydrochloride 1 mg/kg q3H, IM as necessary for pain
Usual Care Access to promethazine hydrochloride 25 mg, plus meperidine hydrochloride 1 mg/kg q3H, IM as necessary for pain 1. Pain 0–10 NRS, measured day 1, 2, 3 post-surgery
2. Narcotic consumption
Bourne et al. [32] Randomised, placebo-controlled, double-blind trial. 2 arm trial. Sponsorship: Sheffield Teaching Hospital Department of Pharmacy and Medicines Management. N = 25 (intervention n = 13, placebo n = 12); female (%), 42%/67%. Age, 58.7 years (SD12.5) /69.9 years (SD12)
Surgery: tracheostomy.
Melatonin, oral.
10 mg oral liquid melatonin, administered at 21:00 h for 4 nights
Placebo, oral.
10 mg liquid placebo, administered at 21:00 h for 4 nights
1. Richards Campbell Sleep Questionnaire
-Sleep efficiency measured with EEG (and evaluated for agreement and reliability with actigraphy), measured at nights 3 and 4.
Egan et al. [27] Randomised, placebo-controlled, double-blind trial. 2 arm trial. Sponsorship: none. N = 40 (2 groups of 20); female (%), 100%/100%.
Age, 42.9 years (SD12.2) /49.6 years (SD14.5).
Surgery: abdominal total hysterectomy.
Benzodiazepine, midazolam IV.
0.125 mg midazolam.
Access to PCA pump containing morphine 1 mg on demand (lockout period 8 min)
Placebo infusion.Access to PCA pump containing morphine 1 mg on demand (lockout period 8 min) 1. Pain 10 cm VAS, measured days 1 and 2 post surgery, between 13:00–15:00 h
2. Level of pain control (morphine) consumed
Gögenur et al. [33] Randomised, placebo-controlled, double-blind trial. 2 arm trial. Sponsorship: none. N = 136 (2 groups of 68); female (%), 68%/74%.
Age, 44 years (SD13)/47 years(SD12)
Surgery: laparoscopic cholecystectomy
Melatonin, oral.
Three capsules of melatonin (each containing 5 mg)
Over 3 nights
Received 2.5–5.0 mg of Morphine IV.
For post-op nausea .625 mg properidol and 1 mg ondansetron IV if necessary. Post discharge 8 mg lornoxicam 2 times a day at 20:00 h and 08:00 h for 4/7 and 5 mg ketobemidon as rescue analgesia
Placebo, oral.
Three capsules of placebo (200 mg of lactose and 3 mg magnesium stearate) over 3 nights
Received 2.5–5.0 mg of morphine IV.
For post-op nausea .625 mg properidol and 1 mg ondansetron IV if necessary.
Post discharge 8 mg lornoxicam 2 times a day at 20:00 h and 08:00 h for 4/7 and 5 mg ketobemidon as rescue analgesia
1. Pain 100 mm VAS, on waking and 20:00 h, on nights 1, 2 and3 post-surgery.
2. Self-reported sleep quality questionnaire 100 mm VAS, in am
-Self report sleep quality via sleep diary, completed in am
3. Fatigue 100 mm VAS, on waking and at 20:00 h
4. General wellbeing on 100 mm VAS, on waking and at 20:00 h
Gong et al. [28] Randomised, placebo-controlled, single-blind trial. 2 arm trial. Sponsorship: none. N = 148 (2 groups of 74); female (%), 87%/ 83%.
Age, 64.8 years (SD5.3)/66.1 yrs(SD5.9)
Surgery: TKR
Non-benzodiazepine
Zolpidem, oral.
5 mg zolpidem orally, at bed time for 14 nights
Received tramadol 100 mg 3 times a day. Oxycodone and access to acetaminophen tablets (5 mg/325 mg) PRN
Placebo oral, at bed time, for 14 nights
Received tramadol 100 mg 3 times a day. Oxycodone and access to acetaminophen tablets (5 mg/325 mg) PRN
1. Pain 0–10 VAS. Score as recall of previous night, measured at days 1, 3, 5, 7, 11 and14 post-surgery
2. Pain control consumption
3. Sleep Efficiency (PSG)
Hershberger and Milad [34]. Randomised, placebo-controlled, double-blind trial. 2 arm trial. Sponsorship: Institutional grant from Dept. of Obstetrics and Gynaecology, Northwestern University Feinberg School of Medicine. N = 97 (intervention n = 49, placebo n = 48); female (%), 100%/100%.
Age, 36 years (SD10)/35 years (SD6).
Surgery: ambulatory gynaecological surgeries
Benzodiazepine, lorazepam IV.
1 mg lorazepam IV (single dose, 1 h post-surgery)
Access to IV hydromorphone or intramuscular (IM) meperidine or IM fentanyl for pain control
Placebo, IV.
1 mg saline IV (single dose,1 h post-surgery)
Access to IV hydromorphone or IM meperidine or IM fentanyl for pain control
1. Pain 0–10 VAS (number of pain score values recorded varied, but averaged 3, time varied, up to 8 h post op)
2. Narcotic consumption, mg of hydromorphone
Jacobsen et al. [29] Randomised, placebo-controlled, double-blind trial. 2 arm trial. Sponsorship: none. N = 100 (intervention n = 49, placebo n = 51); female (%) 100%/100%. Age, 49.9 years (SD10.5)/50.6 years (SD9.75).
Surgery: breast resection, axillary node dissection or mastectomy.
Benzodiazepine, triazolam, oral.
0.125 mg triazolam 3 consecutive nights post op, with option to increase to 0.25 mg after 1 night
Received morphine, meperidine, ibuprofen, acetaminophen and/or acetaminophen with codeine, oxycodone or propoxyphene
Placebo, oral.
0.125 mg placebo, permitted an increase to 0.25 mg
Received morphine, meperidine, ibuprofen, acetaminophen and/or acetaminophen with codeine, oxycodone or propoxyphene
1. Sleep quality 100 mm VAS
-Estimate TTS/sleep latency (min)
-Number of awakenings
-100 mm VAS difficulty falling asleep
-100 mm VAS how rested they felt in the morning, every morning following 3 nights
Krenk et al. [24] Randomised, placebo-controlled, double-blind trial. 2 arm trial. Sponsorship: Lundbeck Foundation Research Grant. N = 22 (2 groups of 11); female (5%), 50%/70% overall.
Age, 70.9 years (SD4.5)/70.5 years (SD5.5).
Surgery: fast-track total hip replacement (THR) or total knee replacement (TKR)
Non-benzodiazepine
Zolpidem, oral.
Oral zolpidem 10 mg, administered 1 h prior to lights-out on day 1 post-op.
Received celecoxib 200 mg, slow release acetaminophen 2 g twice daily and 300 mg gabapentin in the morning and 600 mg in the evening.
Placebo, oral.
Received celecoxib 200 mg, slow release acetaminophen 2 g twice daily and 300 mg gabapentin in the morning and 600 mg in the evening.
1. Pain 0–100 mm VAS, morning of day 1
2.Narcotics consumed, mg of morphine
3. Subjective sleep quality 0–10 NRS
-Objective sleep measures including TST, sleep period time (SPT), awake time (AT)
4. Fatigue 0–10 NRS
Nott et al. [26] Randomised, placebo-controlled, double-blind trial. 4 arm trial. Sponsorship: none. N = 80 (4 groups of 20); female (%): 0%/0%/0%/0%.
Age, 71.7 years (SD9.8)/75.5 years (SD9.5)/71.2 years (SD8.2)/71.9 years (SD8.9).
Surgery: uncomplicated transurethral prostatectomy
Group 1
Benzodiazepine
Diazepam, oral.
Oral diazepam 4 mg 3 times daily
OR
Group 2
Benzodiazepine in combination.
Diazepam, oral.
Oral diazepam and single epidural injection of 10 ml bupivacaine.
All groups received IM pethidine 0.05–0.125 mg/kg with prochlorperazine 12.5 mg if needed or dextropropoxyphene 32.5 mg with paracetamol 325 mg
Group 3
Usual care
OR
Group 4
Usual care.
Single epidural injection of 10 ml of bupivacaine
All groups received IM pethidine 0.05–0.125 mg/kg with prochlorperazine 12.5 mg if needed or dextropropoxyphene 32.5 mg with paracetamol 325 mg
1. Pain (during irrigation) 0–2 scale (0 = no sensation, 1 = aware only, 2 = painful), within 2 days post-surgery
2. Narcotic consumption
Riediger et al. [35] Randomised, placebo-controlled, double-blind trial. 2 arm trial. Sponsorship: University of Basel. N = 24 (2 groups of 12); female (%), 63%/54%
Age, 76 (SD11.75)/68 (SD10)
Surgery: decompression for lumbar spine stenosis.
Benzodiazepine in combination.
Midazolam, intranasal spray.
6 mg S-ketamine base and 0.5mcg chitosan-HCL/0.1 mL spray, with 0.75 mg midazolam intranasal unit-dose spray and 0.5mcg chitosan-HCL/0.1 mL per dose and placebo PCA.
Received 1 g paracetamol orally every 6 h, access to IV metamizole 1 g rescue medication, 6 h lock out
Placebo
2 mg morphine IV PCA and placebo intranasal spray (saline 0.9% and 0.5mcg chitosan-HCL)Received 1 g paracetamol orally every 6 h
Access to IV metamizole 1 g rescue medication, 6 h lock out
1. Pain 0–10 NRS, measured at 1, 2, 4, 24, 48 and 72 h post-surgery
2. Narcotic consumption
Sajedi et al. [30] Randomised, placebo-controlled, double-blind trial. 3 arm trial [Intervention (I), intra-articular (IA), I intramuscular (IM), placebo (P)] Sponsorship: Research Dept. University of Medical Sciences, Isfahan. N = 75 (3 groups of 25); female (%), 21%/20%/12%.
Age, 26.9 years (SD5.4)/27.6 years (SD4.7)/27.5 years (SD5.1).
Surgery: knee arthroscopy.
Group 1-IA (Benzodiazepine, midazolam intravenously (IV)).
Midazolam (75mc/kg) and intra-articular isotonic saline (single dose)
Access to inhalation of isoflurane (1–2%) and morphine (0.1 mg/kg) as additional anaesthesia
OR
Group 2-IV Benzodiazepine, midazolam intra-articular (IA).
Midazolam (75mc/kg) and 10 cc IV isotonic saline (single dose)
Access to inhalation of isoflurane (1–2%) and morphine (0.1 mg/kg)
Placebo IV and IA
Access to inhalation of isoflurane (1–2%) and morphine (0.1 mg/kg)
1. Pain 0–10 VAS, at 2, 4, 8, 12 and 24 h
2.Analgesic consumption over 24 h
Singh et al. [36] Randomised, placebo-controlled trial. 3 arm trial.
Sponsorship: none.
N = 105 (3 groups of 35); female (%), 60%/63%/54%
Age, 40 years (SD6.27)/38 years (SD7.11)/39 years (SD6.27).
Surgery: upper abdominal surgery
Group 1
Benzodiazepine, diazepam, IM.
Diazepam 10 mg IM (single dose)
OR
Group 2
Benzodiazepine, diazepam, IM.
Diazepam 5 mg and morphine 5 mg, IM (single dose)
Morphine, IM.
Morphine 10 mg IM (single dose)
1. Pain estimated by patient, 0–4 scale at 30, 60, 90 and120 min post-surgery
-pain estimated by observer, 0–4 scale at 30, 60, 90 and 120 min post-surgery
Tashjian et al. [25] Randomised, placebo-controlled, double-blind trial. 3 arm trial. Sponsorship: none. N = 68 (intervention n = 24, control n = 24, placebo n = 19); female (%), 21%/26%/38% overall.
Age, 49.2 years/47.5 years/47 years
Surgery: knee arthroscopy.
Group 1
Non-benzodiazepine in combination
Zolpidem, oral.
7 zolpidem tartrate tablets (10 mg)
40 hydrocodone/acetaminophen bi-tartrate tablets (7.5 mg/750 mg) for the first 7 postoperative days.
Access to Ibuprofen 800 mg PRN
Group 2
Placebo, oral.
Placebo and 40 hydrocodone/acetaminophen bi-tartrate tablets (7.5 mg/750 mg)
Access to Ibuprofen 800 mg PRN
OR
Group 3
Usual care
40 hydrocodone/acetaminophen bi-tartrate tablets (7.5 mg/750 mg) Access to ibuprofen 800 mg PRN.
1. Pain 0-10 VAS measured morning and night for first 7 days
2. Pain control (hydrocodone/acetaminophen) consumed
3. Fatigue 0–10 VAS, measured morning and night for first 7 days
Tompkins et al. [22] Randomised, placebo-controlled, double-blind trial. 2 arm trial. Sponsorship: Smith & Nephew. N = 29 (intervention n = 13, control n = 16); female (%), 38%/56%.
Age, 36.9 years/35.6 years.
Surgery: primary arthroscopic ACL reconstruction.
Group 1
Non-benzodiazepine
Zolpidem, oral.
Zolpidem tartrate tablets (10 mg) taken for the first 7 post-operative days, taken nightly
OR
Group 2
Non-benzodiazepine in combination
Zolpidem, oral.
Oral zolpidem and 40 hydrocodone/acetaminophen bi-tartrate 7.5 mg, to be taken 1–2 tablet every 6 h PRN
Group 3
Placebo, oral
OR
Group 4
Placebo, oral.
Placebo and 40 hydrocodone/acetaminophen bi-tartrate 7.5 mg, to be taken 1–2 tablet every 6 h PRN
1. Pain 0–100 VAS, measured in the morning and evening days 1–7 post-surgery
2. Narcotic consumed, vicodin (and ibuprofen)
3. Fatigue 0–100 VAS, measured in morning and evening days 1–7 post-surgery