Table 1: PEDro ratings for eligible trials PEDro criterion Trials Ahlstrom 1985 Eccles 1992 Frame 1986 Heidrich 1985 Smith 2006 Quiding 1983 Skoglund 1991 Squires 1981 Cater 1985 Gerschman 1984 Giles 1986 Quiding 1992 Freestone 1997 Matthys 1983 1. 0 0 0 0 0 0 0 0 0 1 0 0 1 0 2. 1 1 1 1 1 1 1 1 1 1 1 1 1 1 3. 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4. 1 1 1 1 1 1 1 0 1 0 1 0 1 1 5. 1 1 1 1 1 1 1 1 1 1 1 1 1 1 6. 1 1 1 1 1 1 1 1 1 1 1 1 1 1 7. 1 1 1 1 1 1 1 1 1 1 1 1 1 1 8. 1 1 0 0 1 0 1 0 0 1 1 1 1 1 9. 0 0 0 0 0 0 0 0 0 0 0 0 0 0 10. 1 1 1 1 1 1 1 1 1 1 0 1 1 1 11. 1 1 0 1 1 1 0 0 0 1 0 1 1 1 Total Score 9 9 7 8 9 8 8 6 7 9 7 8 9 9 Legend: 1= the trial complied with the PEDro item, 0= non-compliance. Operational definitions for each PEDro item are provided below.
Figure 4: Treatment effects reported in individual studies at time points from 3 (3 h) to 12hours (12h) The blue dots signify treatment effects >10-points which are considered clinically worthwhile. Note Quiding et al., 1992 [53]; results are for average pain over 8 hours following 1st dose and 6th dose. The 6th dose was measured from 24 - 32hours. * Study reported the mean pain intensity difference over the follow up period specified. ** Study used a multiple dose regimen. Table 2: Characteristics of included studies Study Setting / Country Indication Mean age of participants Participant Characteristics (number entered) Intervention [Randomised, double blind, parallel group] Control Outcome Measure Follow Up period (post ingestion) Pain Trials Ahlstrom 1985 Stockholm Sweden Surgical removal of an impacted wisdom I (A): 31 I (B): 29 P (C): 27 P (D): 28 I (A): 44 I (B): 43 Placebo: 85 F: 82 M: 90 I (A): paracetamol 1000 mg + codeine 60 mg I (B): paracetamol 500 mg + codeine 30 mg A second dose could be taken Placebo 0-10 VAS 12 h 1985 Nottingham England Post episiotomy pain I: 23.1 P: 22.7 I: 46 P: 47 single dose study Ibuprofen 400 mg + codeine 30 mg n=46 Placebo 9 point pain rating scale i.e. 0-8 8 h Frame 1986 Queensway Birmingham Removal of an impacted mandibular third molar tooth I (C): 23.55 I (D):25.09 I (E): 23.70 P (A): 23.55 I (C): 33 I (D):33 I (E): 33 P (A): 33 single dose study I (C): 33 ibuprofen 200 mg + codeine 15 mg I (D):33 ibuprofen 400 mg + codeine 30 mg I (E): 33 ibuprofen 800 mg + codeine 60 mg P (A): 33 Placebo 9 point pain rating scale i.e. 0-8 5 h
Gerschman 1984 Copenhagen Temporomandibular joint pain dysfunction syndrome I: 34.6 P: 29.7 I: 14 P: 16 Paracetamol 450 mg + codeine 9.75 mg 2 tabs every 4 hours Placebo VAS 0-100 2 weeks (cross over study design) Giles 1986 Nottingham England Postoperative dental pain I: 23.9 P: 25.7 I: 36 P: 35 Single dose study Ibuprofen 200 mg + codeine 15 mg Placebo 9 point pain rating scale i.e. 0-8 5 h Heidrich 1985 Washington Post-orthopaedic surgery patients with moderate to severe pain. 31 years across entire cohort I: 40 P: 40 Single dose Paracetamol 300 mg + codeine 30 mg Placebo VAS 0-100 6 h Quiding 1983 Sweden Post meniscectomy I: 33 (9.6) P: 38 (11.3) I: 16 P:10 Single dose study paracetamol 1000 mg + codeine 60 mg Placebo Pain intensity Difference 0-10 6 h Skoglund 1991 Norway Post-surgery to remove impacted wisdom I: 25 P: 24.4 I: 37 P 33 Single dose study paracetamol 1000 mg + codeine 60 mg Placebo VAS 0-100 6 h Squires 1981 Canada Dental surgery pain I: 27.0 P: 28.7 I: 30 P: 26 Single dose study ASA-30 (Aspirin 375 mg + codeine 30 mg + caffeine 30 mg) Placebo 9 point pain rating scale i.e. 0-8 4 h Quiding 1992 Sweden Coxarthrosis 53 I: 26 P: 26 M: 4 F: 22 I (A): ibuprofen 200 mg + codeine 30 mg Six doses during 24 hours Placebo 0-100 VAS 32 h Cough Trials Smith 2006 (cross-over design) United Kindgdom in COPD 68.0 (6.86) 21 I: 19 P: 19 Codeine phosphate 60 mg capsules and again after 12 hours Placebo Cough frequency (coughs/hour) 12 h (day and night) trial
14 Male Cough symptom score (0-100 VAS) Matthys 1983 Germany Chronic stable cough due to pulmonary tuberculosis, bronchial carcinoma or obstructive lung disease 55.9 (17.2) 16 M: 11 F: 5 2 doses of codeine phosphate 20 mg for three consecutive nights Placebo Cough frequency (per hour) 8 h Eccles 1992 Wales, Cardiff Cough associated with acute upper respiratory tract infection 23 91 M: 47 F: 44 Codeine 30 mg / 10 mL four times a day up to 120 mg codeine / day Placebo Cough frequency per minute Cough severity (0-100 VAS) ~ 3 h (150 minutes) Freestone 1997 Cardiff, UK Cough associated with upper respiratory tract infection 23.5 82 F: 51 M: 31 Single dose of codeine 50 mg capsules Placebo Cough frequency 90 minutes I: Intervention; P: Placebo
Friday et al., 2009. Extremity injuries 10 cm colour analogue (1 mg⁄ kg as codeine, maximum 60 mg) n=32 or ibuprofen (10 mg⁄ kg, maximum 400 mg) n=34 In children presenting to ED with moderate to severely painful extremity injuries, there was adequate and equivalent analgesia with ibuprofen or the paracetamol−codeine combination. Note differences favour ibuprofen in the first 40 minutes and the combination at 1 hour. Results were not statistically significant based on 95% CI. Gatoulis et al., 2012. Third molar extraction or tension type headache Pain Intensity Difference on verbal rating scale Aspirin (1000 mg), acetaminophen (300 mg) + codeine (30 mg), or placebo Treatment with aspirin (1000 mg) provides statistically significant analgesia compared with placebo use and comparable efficacy with acetaminophen (300 mg) + codeine (30 mg) therapy after impacted third molar extraction and in tension- type headache. Hellman et al., 1992. Removal of lower third molars VAS Two-dose regimen: combination ibuprofen 200 mg + codeine 30 mg was compared with that of acetylsalicylic acid 500 mg + codeine 30 mg and codeine 30mg The combination ibuprofen-codeine had greater analgesic efficacy compared to the combination acetylsalicylic (P<0.005) or codeine in patients with pain after removal of the lower third molars. Madore et al., 1967. Post-operative pain Pain Intensity Difference on rating scale Fiorinal with codeine Double dose of Fiorinal was superior to the single dose. Matts et al., 1966. Recurring pain Sequential Analysis Chart Panadeine Co (paracetamol 1 g plus codeine phosphate 16 mg) vs soluble aspirin 1 g Panadeine Co was superior to soluble aspirin in obtaining pain relief.
Ragg et al., 1997. Premedication and analgesia for myringotomy in children 4 point pain face rating scale Paracetamol vs Painstop (paracetamol 12 mg, codeine 0.5 mg and promethazine 0.65 mg per ml) 30 to 60 minutes prior to surgery Pain scores were similar in both treatment arms. Little need for additional analgesia p<0.03. Skjelbred et al., 1982. Oral surgical procedures 100 mm VAS Paracetamol + codeine phosphate (400 mg + 30 mg), vs plain paracetamol (400 mg) No increase in analgesia was demonstrated by the addition of codeine to paracetamol. The majority of participants (n=20) preferred treatment with plain paracetamol over the combination (n-4) p<0.001. Sniezek et al., 2011. Postoperative pain relief VAS Patients undergoing MMS and reconstruction for head and neck skin cancers received 1 g paracetamol paracetamol plus 400mg ibuprofen, or 325mg paracetamol plus 30mg codeine immediately after surgery and every 4 hours for up to four doses The group administered the combination of paracetamol + ibuprofen had the lowest pain scores (mean change from baseline/immediately prior to surgery) at each postoperative recorded time interval and a significantly smaller change from baseline pain scores than the paracetamol + codeine group at 4 hours (p = 0.005) and the paracetamol group at 8 hours (p = 0.02). Walton et al., 1990 Post-operative oral surgery pain Five point verbal rating scale Ibuprofen 300 mg tablets vs ibuprofen 300 mg + codeine 20 mg tablets There was no statistically significant difference in the effectiveness of either preparation in the control of postoperative pain. Both preparations were reported to provide good pain relief throughout the study.
Appendix Table 2: Data Extraction Table Treatment Mean (SD) N Placebo Mean (SD) N Mean Difference Clinically Significant Heidrich 1985 – post orthopaedic surgery Paracetamol 300 mg + codeine 30 mg VAS 0-100 3 h 6 h Median SD value used 54 (22.2) 71 (22.2) 40 40 65 (22.2) 68 (22.2) 40 40 -11.0 (-20.7, -1.3) 3.0 (-6.7, 12.7) Yes No Ahlstrom 1985 Paracetamol 1000 mg + codeine 60 mg (treatment A) PID 12h Paracetamol 500 mg + codeine 30 mg (treatment B) PID 12h Median SD used 15 (22.2) 30 (22.2) 44 43 46 (22.2) 46 (22.2) 85 85 -31.0 (-39.1, -22.9) -16.0 (-24.1, -7.9) YES YES Giles 1986 (Median SD used) Ibuprofen 200 mg + codeine 15 mg 0-9 pain rating 3h 5h 0-100 3h 5h 2.2 2.4 27.5 (22.2) 30 (22.2) 36 36 36 36 3.5 2.5 43.8 (22.2) 2.5 (22.2) 35 35 35 -16.3 (-26.6, -6.0) -1.3 (-11.6, 9.0) Yes No Skoglund 1991 Codeine 60 mg paracetamol 1000 mg PI VAS 0-100 3h 6h Median SD value used 21 (22.2) 27 (22.2) 37 37 47 (22.2) 42 (22.2) 33 33 -26.0 (-36.4, -15.6) -15.0 (-25.4, -4.6) Yes Yes
Squires 1981 (dental surgery) (ASA 375mg + codeine 30mg + caffeine 30 mg) 9 point rating scale PID 3h SD converted and used from baseline 1.2 15 (20) 30 1.9 23.8 (16.3) 26 -8.8 (-18.31, 0.71) No Quiding 1983 Single dose of paracetamol 1000 mg codeine 60 mg Mean PI (over 4 h) 44 (13.6) 16 51 (24.4) 10 -7.0 (-23.53, 9.53) No Gerschman 1984 Paracetamol 450 mg + codeine 9.75 mg (2 tabs 4 hourly) _end of treatment Mean Difference in Pain VAS 0-100 -45.4 (24.8) 14 -19.4 (27.0) 16 -26.0 (-44.54, -7.46) Yes Cater 1985 Ibuprofen 400 mg + codeine 30 mg 3h 0-8 0-100 6h 0-8 0-100 8 h 0-8 0-100 Median SD value used 2.4 30 (22.2) 2.8 35 (22.2) 3.5 43.8 (22.2) 46 46 46 3.2 40 (22.2) 3.3 41.3 (22.2) 3.2 40 (22.2) 47 47 47 -10.00 (-19.0, -1.0) -6.3 (-15.3, 2.7) 3.80 (-5.2, 12.8) No No No Frame (1986) Ibuprofen 200 mg + codeine 15 mg 9 point rating scale (Intervention C) 3h 0-8 0-100 2.43 30.38 (22.2) 32 3.42 42.75 (22.2) 26 -12.4 (-23.9, -0.9) Yes
(Intervention C) 5h 0-8 0-100 Frame Ibuprofen 400 mg + codeine 30 mg (Intervention D) 3 h 0-8 0-100 (Intervention D) 5 h 0-8 0-100 – third molar Ibuprofen 800 mg + codeine 60 mg (Intervention E) 3h 0-8 0-100 (Intervention E) 5 h 0-8 0-100 Median SD value used 2.28 28.5 (22.2) 2.21 27.6 (22.2) 1.66 20.8 (22.2) 1.96 24.5 (22.2) 2.22 27.8 (22.2) 32 33 33 26 26 2.56 32 (22.2) 3.42 42.75 (22.2) 2.56 32 (22.2) 3.42 42.75 (22.2) 2.56 32 (22.2) 26 26 26 26 26 -3.5 (-15.0, 8.0) -15.2 (-26.6, -3.8) -11.2 (-22.6, 0.2) -18.3 (-30.4, -6.2) -4.2 (-16.3, 7.9) No Yes Yes Yes No Quiding 1992 Median SD value used Ibuprofen + codeine Mean VAS 1-8 h after first dose 0-8 h after 6th dose 25 (22.2) 10 (22.2) 26 26 26 (22.2) 29 (22.2) 26 25 -1.0 (-13.1, 11.1) -19.0 (-31.2, -6.8) No Yes