Sixteen placebo-controlled studies that involved 3378 subjects suffering from acute pain were analyzed for the efficacy of low-dose codeine (≤ 30 mg) combination products. |
Twenty randomized clinical trials which included at least one dose of codeine (from 30 to 240 mg daily), were analyzed for the safety and adverse-effects profile. |
In EudraVigilance database for the 10-year time period, a total of 20 individual case safety reports for dependence were identified with codeine as a suspect drug. |
Low-dose codeine in fixed combinations with other drugs is effective and safe when used as recommended. |
There is no exact proof in the available literature that clearly links low doses of codeine to substance use disorder issues in non-dependent subjects. |
Introduction
Methods
General Search Strategy
Study Selection
Efficacy Study Search and Selection
Safety Study Search and Selection
Data Extraction and Quality Assessment
Results
Overview of Efficacy
Authors (reference) | Study design | Number of participants | Population characteristics/Mean age of the participants (years) | Indication | Intervention (compared to placebo) | Outcome measures | Analgesic efficacy period measurement (h) | Study conclusion on codeine/codeine combinations compared to comparator/placebo |
---|---|---|---|---|---|---|---|---|
Cooper and Beaver [15] | A randomized, double-blind, single-dose study | 128 | 64 Female and 64 male patients/aged between 16 and 35 | Oral surgery pain | 1. Ibuprofen 400 mg + codeine phosphate 30 mg 2. zomepirac 100 mg 3. codeine 30 mg 4. acetylsalicylic acid 650 mg 5. codeine 30 mg + acetylsalicylic acid 650 mg | Pain relief Pain intensity difference | 3 | Low-dose codeine combination is more efficient in relieving pain compared to placebo, acetylsalicylic acid 650 mg and codeine 30 mg alone |
Cater et al. [26] | A double-blind, single-dose study | 127 | All female patients/22.8 | Moderate or severe postepisiotomy pain | 1. ibuprofen 400 mg + codeine phosphate 30 mg 2. zomepirac 100 mg 3. codeine 30 mg 4. acetylsalicylic acid 650 mg 5. codeine 30 mg + acetylsalicylic acid 650 mg | Degree of pain Pain relief Pain half gone | 8 | Low-dose codeine combination is more efficient in relieving pain compared to placebo and zomepirac 100 mg |
Heidrich et al. [27] | A double-blind, single-dose, parallel-group | 120 | 48 Female and 72 male patients/31 | Post-orthopaedic surgery pain | 1. ibuprofen 400 mg 2. paracetamol 300 mg + codeine 30 mg | Pain relief Pain intensity Mood | 6 | Codeine in combination is effective, but less than the comparator |
Frame et al. [19] | A double-blind, single dose study | 165 | Both genders were included/24.4 | Removal of an impacted mandibular third molar tooth | 1. acetylsalicylic acid 600 mg 2. ibuprofen 200 mg + codeine phosphate 15 mg 3. ibuprofen 400 mg + codeine phosphate 30 mg 4. ibuprofen 800 mg + codeine phosphate 60 mg | Pain relief (degree of pain) | 5 | Low-dose codeine combinations are more efficient in relieving pain compared to placebo and acetylsalicylic acid |
Desjardins et al. [17] | A double-blind, randomized, single-dose study | 123 | 77 Female and 46 male patients/23.8 | Oral surgery pain | 1. paracetamol 300 mg + codeine 30 mg 2. acetylsalicylic acid 325 mg + butalbital 50 mg + caffeine 40 mg + codeine 30 mg | Sum of pain intensity difference (SPID) Peak pain intensity difference Total pain relief (TOTPAR) Peak pain relief Sum of observations with pain half gone Total anxiety Peak anxiety Total relaxation Peak relaxation Overall evaluation Time to remedication with an alternate analgesic | 6 | Low-dose codeine combinations are more efficient in relieving pain than placebo |
Forbes et al. [18] | A double-blind, parallel group, randomized study | 122 | 77 Female and 45 male patients/21.63 | Moderate or severe pain after the surgical removal of impacted third molars | 1. acetylsalicylic acid 325 mg + caffeine 40 mg + codeine 30 mg + butalbital 50 mg 2. paracetamol 300 mg + codeine 30 mg | Pain intensity difference score (PIO) Sum of the pain intensity difference scores (SPIO) Peak PIO score Pain relief score Total pain relief score Peak pain relief score Total hours of 50% relief Overall evaluation Anxiety difference score Sum of the anxiety difference scores Peak anxiety difference score Relaxation difference score Sum of the relaxation difference scores Peak relaxation difference score Time until taking the backup medication | 6 | Low-dose codeine combinations are more efficient in relieving pain than placebo |
Giles et al. [22] | A double-blind, single dose study | 202 | Both genders were included/24.8 | Surgical removal of third molars pain | 1. acetylsalicylic acid 600 mg 2. ibuprofen 200 mg 3. codeine 15 mg 4. ibuprofen 200 mg + codeine 15 mg | Degree of pain Pain relief If the pain was half gone | 5 | Codeine, alone or in combination, has little to none analgesic efficacy |
Hwang et al. [24] | A randomized, double-blind, placebo-controlled, multicenter trial | 208 | Both genders were included/aged between 18 and 65 | Tension headache | 1. butalbital 50 mg + caffeine 40 mg + acetylsalicylic acid 200 mg + phenacetin 130 mg 2. codeine phosphate 30 mg 3. butalbital 50 mg + caffeine 40 mg + acetylsalicylic acid 200 mg + phenacetin 130 mg + codeine 30 mg | Patients’ self-evaluation: Pain severity Pain relief Tension and uptight feeling Relaxation and contentment Muscle stiffness Daily activities Average tension composite Average pathology Physician’s global evaluation: Headache pain Psychic tension Muscle contraction | 4 | Low-dose codeine combinations are more efficient in relieving pain compared to placebo, butalbital 50 mg + caffeine 40 mg + acetylsalicylic acid 200 mg + phenacetin 130 mg and codeine phosphate 30 mg |
Petti et al. [29] | A single-blind, parallel-group study | 129 | Both genders were included/aged between 18 and 80 | Moderate postoperative pain | 1. paracetamol 650 mg + pentazocine 25 mg 2. paracetamol 300 mg + codeine 30 mg 3. paracetamol 650 mg + propoxyphene napsylate 100 mg | Severity of pain Degree of pain relief | 6 | Low-dose codeine combination is more efficient in relieving pain compared to placebo, paracetamol 650 mg + pentazocine 25 mg and paracetamol 650 mg + propoxyphene napsylate 100 mg |
Giglio and Laskin [21] | A single-dose, randomized, double-blind, parallel-treatment study | 200 | 165 Female and 35 male patients/22.7 | Surgical removal of third molars pain | 1. meclofenamate 100 mg + codeine 60 mg 2. meclofenamate 50 mg + codeine 30 mg 3. meclofenamate 100 mg 4. codeine 60 mg | Pain intensity difference (PID) Sum of pain intensity differences (SPID) Sum of pain relief scores (TOTPAR) Peak pain relief Number of observations at which pain was half relieved Overall evaluation of study medication effectiveness Time to remedication with a backup analgesic | 6 | Low-dose codeine combination is more efficient in relieving pain compared to placebo and codeine 60 mg, but slightly less efficient than meclofenamate 100 mg and meclofenamate 100 mg + codeine 60 mg |
Boureau et al. [25] | A randomized, multicentre, double-blind study | 247 | 190 Female and 57 male patients/40.1 ± 11.6 | Acute migraine attack | 1. paracetamol 400 mg + codeine 25 mg 2. acetylsalicylic acid 1000 mg | Complete or near complete relief of pain | 2 | Low-dose codeine combination is more efficient in relieving pain compared to placebo and slightly less efficient than acetylsalicylic acid 1000 mg |
Daniels et al. [16] | A double-blind, 5-arm, parallel-group, placebo-controlled, randomised, single-dose study | 678 | 105 Female and 68 male patients/20.2 | Postoperative dental pain | 1. ibuprofen 200 mg + paracetamol 500 mg | Pain relief Pain intensity difference | 12 | Codeine in combinations is effective, but less than the comparator ibuprofen + paracetamol combination |
Gatoulis et al. [20] | A randomized, double-blind, placebo-controlled, single-dose clinical trial | 302 | 185 Female and 115 male patients/23.13 | Dental pain | 1. acetylsalicylic acid 1000 mg 2. paracetamol 300 mg + codeine 30 mg | Sum of pain intensity differences from baseline (SPID) The time-interval–weighted sum of pain relief scores (TOTPAR) Pain intensity difference (PID) Peak PID Pain relief score (PAR) Peak PAR Time to onset of meaningful and complete relief Time to use of rescue medication | 6 | Low-dose codeine combination is more efficient in relieving pain compared to placebo and comparably efficient compared to acetylsalicylic acid 1000 mg |
676 | 304 Female and 183 male patients/37.12 | Tension-type headache | 4 | |||||
Cristalli et al. [10] | A randomized, placebo-controlled, double-blind | 32 | Both genders were included/aged between 20 and 29 | Mandibular third molar surgery pain | Paracetamol 500 mg + codeine 30 mg | Postoperative pain The number of patients using rescue therapy, Time to the first use of rescue analgesia Total number of postoperative-supplement paracetamol + codeine tablets | 48 | Low-dose codeine combination is more efficient in relieving pain than placebo |
Pereira et al. [28] | A randomized, double-blind, placebo-controlled add-on trial | 40 | 27 Female and 13 male patients/30 | Pain after photorefractive keratectomy | Codeine 30 mg + paracetamol 500 mg | Difference in pain intensity Mean pain scores | 72 | Low-dose codeine combination is more efficient in relieving pain compared to placebo |
Overview of Safety
Studies | Treatment | Comparator | Study conclusion | Number of patients reporting adverse drug reactions (n/N) | ||
---|---|---|---|---|---|---|
Treatment (n/N) | Comparator (n/N) | Treatment vs. comparator | ||||
Cooper et al. [33] | I. codeine 60 mg, II. acetylsalicylic acid 650 mg + codeine 60 mg, III. ibuprofen 400 mg + codeine 60 mg | A. acetylsalicylic acid 650 mg, B. ibuprofen 400 mg, C. placebo | There were no significant differences regarding AEs within treatment groups. No withdrawal from the study was recorded | I. 26.8% (11/41) II. 26.7% (12/45) III. 43.9% (18/41) | A. 23.7% (9/38) B. 28.9% (11/38) C. 10.9% (5/46) | 32.3% vs. 20.5% |
Forbes et al. [34] | Paracetamol 600 mg + codeine 60 mg | A. diflunisal 500 mg, B. diflunisal 1000 mg, C. paracetamol 600 mg, D. placebo | There were no significant differences regarding AEs within treatment groups | 42.3% (11/26) | A. 46.2% (12/26) B. 46.4% (13/28) C. 42.3% (11/26) D. 15.4% (4/26) | 42.3% vs. 37.7% |
Desjardins et al. [17] | I. paracetamol 300 mg + codeine 30 mg, II. acetylsalicylic acid 325 mg + butalbital 50 mg + caffeine 40 mg + codeine 30 mg | Placebo | There were no significant differences regarding AEs within treatment groups | I. 5.1% (2/39) II. 11.6% (5/43) | 9.8% (4/41) | 8.5% vs 9.8% |
Forbes et al. [18] | I. codeine sulfate 60 mg, II. naproxen sodium 550 mg + codeine 60 mg | A. naproxen sodium 550 mg, B. acetylsalicylic acid 650 mg, C. placebo | Report includes AEs occurred within 12 h of taking study medication. Incidence of AEs was higher in codeine treatment groups | I. 25.5% (12/47) II. 35.6% (16/45) | A. 16.3% (7/43) B. 7.3% (3/41) C. 15.2% (7/46) | 30.4% vs. 13.1% |
Sagne et al. [35] | Paracetamol 650 mg + codeine 60 mg | Paracetamol 650 mg + dextropropoxyphene 65 mg | Adverse events were more frequent in women from paracetamol + codeine group | 38.1% (37/97) | 26.6% (25/94) | 38.1% vs. 26.6% |
Stambaugh and Drew [36] | Acetylsalicylic acid 650 mg + codeine 60 mg | A. ketoprofen 100 mg, B. ketoprofen 300 mg, C. placebo | There were no significant differences in relation with safety data within treatment groups | 22.5% (9/40) | A. 17.5% (7/40) B. 17.5% (7/40) C. 22.5% (9/40) | 22.5% vs. 19.2% |
Sunshine et al. [37] | Codeine 60 mg | A. piroxicam 20 mg, B. placebo | The highest incidence of reported AEs was observed in the placebo group | 19.6% (10/51) | A. 14.0% (7/50) B. 50.0% (25/50) | 19.6% vs 32.0% |
Turek et al. [38] | Paracetamol 650 mg + codeine 60 mg | A. ketoprofen 50 mg, B. ketoprofen 150 mg, C. placebo | There was a significantly greater incidence of central nervous system AEs in the paracetamol plus codeine group | 28.2% (11/39) | A. 34.1% (14/41) B. 20.5% (8/39) C. 9.8% (4/41) | 28.2% vs. 21.5% |
Forbes et al. [39] | Paracetamol 600 mg + codeine 60 mg | A. flurbiprofen 100 mg, B. paracetamol 600 mg, C. placebo | Report includes AEs occurred within 12 h of taking study medication | 5.9% (1/17) | A. 3.4% (1/29) B. 11.5% (3/26) C. 7.7% (2/26) | 5.9% vs. 7.4% |
Minotti et al. [31] | Acetylsalicylic acid 640 mg + codeine 40 mg | A. nefopam 60 mg, B. diclofenac sodium 50 mg | AEs were slightly more frequent within acetylsalicylic acid + codeine and nefopam treatment groups | 36.4% (12/33) | A. 39.4% (13/33) B. 6.1% (2/33) | 36.4% vs. 27.3% |
Carlson et al. [30] | Paracetamol 600 mg + codeine 60 mg | Ketorolac 10 mg | AEs were acceptable for both treatment groups | 47.5% (19/40) | 61.8% (21/34) | 47.5% vs. 61.8% |
Forbes et al. [40] | Paracetamol 600 mg + codeine 60 mg | A. ketorolac 10 mg, B. ketorolac 20 mg, C. ibuprofen 400 mg, D. paracetamol 600 mg, E. placebo | All AEs were transient, and none of them required additional treatment | 20.0% (8/40) | A. 12.8% (5/39) B. 18.6% (8/43) C. 18.6% (8/43) D. 12.2% (5/41) E. 0% | 20.0% vs. 15.7% |
Hellman et al. [41] | I. codeine 30 mg, II. ibuprofen 200 mg + codeine 30 mg, III.acetylsalicylic acid 500 mg + codeine 30 mg | NA | Codeine alone caused a higher rate of AEs than in combinations (17% vs. 11%) | I. 16.7% (8/48) II. 10.6% (5/47) III. 10.3% (4/39) | NA | 12.7% vs. 0% |
Petersen et al. [42] | Ibuprofen 400 mg + codeine 60 mg | Ibuprofen 400 mg | Incidence of AEs were higher in ibuprofen + codeine group | 48.3% (14/29) | 19.4% (6/31) | 48.3% vs. 19.4% |
Stubhaug et al. [43] | Paracetamol 1000 mg + codeine 60 mg | A. tramadol 50 mg, B. tramadol 100 mg, C. placebo | AEs were more common for tramadol treatment groups | 27.0% (10/37) | A. 54.3% (19/35) B. 50.0% (18/36) C. 41.7% (15/36) | 27.0% vs. 49.1% |
Soulier et al. [44] | Paracetamol 300 mg + codeine phosphate 30 mg | Flurbiprofen 50 mg | Differences between 2 groups were not statistically significant | 57.5% (23/40) | 46.3% (19/41) | 57.4% vs. 46.3% |
Innes et al. [45] | Paracetamol 600 mg + 60 mg codeine | Ketorolac 10 mg | Patients in the paracetamol + codeine group reported significantly more AEs; 7 out of 60 patients withdrew from the study because of AEs after 7-day treatment | 64.4% (38/59) | 33.9% (21/62) | 64.4% vs. 33.9% |
Daniels et al. [16] | Paracetamol 2400 mg + codeine 240 mg | A. ibuprofen 2400 mg, B. etoricoxib 90 mg, C. etoricoxib 120 mg, D. placebo | Significantly more discontinuations due to AEs were observed in paracetamol + codeine group | 48.4% (30/62) | A. 9.4% (18/192) B. 11.0% (21/191) C. 12.4% (12/97) D. 13.0% (6/46) | 48% vs. 10.8% |
Gatoulis et al. (2 studies included; 1. and 2.) [20] | Paracetamol 600 mg + codeine phosphate 60 mg | A. acetylsalicylic acid 1000 mg, B. placebo | There were no statistically significant differences regarding AEs and no serious AEs were reported | 1. 31.4% (38/121) | A. 28.3% (34/120) B. 39.3% (24/61) | 31.4% vs. 32.0% |
2. 24.5% (57/233) | A. 17.0% (38/223) B. 18.4% (19/103) | 24% vs. 17.5% | ||||
Mitchell et al. [32] | Paracetamol 600 mg + caffeine 30 mg + codeine 60 mg | Paracetamol 650 mg + ibuprofen 400 mg | There were no significant differences regarding AEs within treatment groups, however, discontinuations due to AEs were higher in the codeine group | 41.4% (29/70) | 42.3% (30/71) | 41.4% vs. 42.3% |