Background
Methods
STOP Pain study
Statistical analyses
Systematic literature review
Results
STOP Pain study
Patient population
Overall | G/Ga | A/Ga | A/Aa |
p-value
b
| |
---|---|---|---|---|---|
N (%) | N (%) | N (%) | N (%) | ||
87 | 24 (30.38) | 42 (53.16) | 13 (16.46) | ||
Gender | |||||
Male | 49 (56.32) | 15 (62.50) | 22 (52.38) | 7 (53.85) | 0.721 |
Female | 38 (43.68) | 9 (37.50) | 20 (47.62) | 6 (46.15) | |
Age (months) | |||||
0–36 | 18 (20.69) | 4 (16.67) | 8 (19.05) | 4 (30.77) | 0.466 |
> 36–144 | 32 (36.78) | 10 (41.67) | 18 (42.86) | 2 (15.38) | |
> 144 | 37 (42.53) | 10 (41.67) | 16 (38.10) | 7 (53.85) | |
BMI (percentile) | |||||
< 25th | 33 (42.31) | 5 (25.00) | 18 (46.15) | 5 (38.46) | 0.490 |
25th- < 75th | 20 (25.64) | 8 (40.00) | 8 (20.51) | 4 (30.77) | |
≥ 75th | 25 (32.05) | 7 (35.00) | 13 (33.33) | 4 (30.77) | |
missing
|
9
| ||||
Diagnosis | |||||
Brain Tumour | 6 (6.90) | 2 (8.33) | 2 (4.76) | – | 0.728 |
Leukaemia and Lymphoma | 34 (39.08) | 11 (45.83) | 18 (42.86) | 4 (30.77) | |
Neuroblastoma | 6 (6.90) | 1 (4.17) | 3 (7.14) | 2 (15.38) | |
Osteosarcoma | 17 (19.54) | 2 (8.33) | 8 (19.05) | 3 (23.08) | |
Sarcoma | 18 (20.69) | 7 (29.17) | 8 (19.05) | 2 (15.38) | |
Others | 6 (6.90) | 1 (4.17) | 3 (7.14) | 2 (15.38) | |
Metastasis | |||||
No | 64 (73.56) | 19 (79.17) | 26 (61.90) | 12 (92.31) | 0.067 |
Yes | 23 (26.44) | 5 (20.83) | 16 (38.10) | 1 (7.69) | |
Pain location | |||||
Abdominal | 12 (13.79) | 5 (20.83) | 4 (9.52) | 2 (15.38) | 0.808 |
Oral cavity | 43 (49.43) | 11 (45.83) | 23 (54.76) | 6 (46.15) | |
Skeletal – Muscle | 14 (16.09) | 3 (12.50) | 5 (11.90) | 3 (23.08) | |
Other | 18 (20.69) | 5 (20.83) | 10 (23.81) | 2 (15.38) | |
Pain Intensity (PIto), mean (95% CI) | 4.34 (3.88–4.81) | 4.08 (3.33–4.84) | 4.57 (3.89–5.25) | 4.38 (2.81–5.96) | 0.674a |
Drug | |||||
morphine | 60 (68.97) | 16 (66.67) | 32 (76.19) | 8 (61.54) | |
tramadol | 19 (21.84) | 5 (20.83) | 9 (21.43) | 3 (23.08) | 0.632 |
oxycodone | 2 (2.30) | 1 (4.17) | – | – | |
codeine | 2 (2.30) | 1 (4.17) | – | 1 (7.69) | |
more than one | 4 (4.60) | 1 (4.17) | 1 (2.38) | 1 (7.69) |
Influence of COMT polymorphism on efficacy and safety parameters
Overall | G/G | A/G | A/A |
p-value
| |
---|---|---|---|---|---|
Opioids | |||||
Dose (mg/kg) | |||||
Dose24h | |||||
mean (95% CI) | 0.38 (0.33–0.42) | 0.41 (0.30–0.52) | 0.39 (0.33–0.45) | 0.36 (0.23–0.48) | |
median (interquartile range) | 0.41 (0.19–0.50) | 0.43 (0.16–0.57) | 0.42 (0.24–0.49) | 0.43 (0.19–0.46) | 0.921* |
Dosetot | |||||
mean (95% CI) | 2.57 (2.17–2.96) | 3.34 (2.45–4.23) | 2.35 (1.83–2.87) | 2.24 (1.11–3.37) | |
median (interquartile range) | 2.18 (1.20–3.50) | 3.25 (1.73–5.23) | 2.02 (1.26–2.97) | 2.18 (1.06–3.07) | 0.119* |
DoseVAS = 0 | |||||
mean (95% CI) | 0.41 (0.27–0.55) | 0.59 (0.18–1.01) | 0.35 (0.22–0.48) | 0.39 (0.03–0.75) | |
median (interquartile range) | 0.26 (0.10–0.49) | 0.36 (0.07–0.74) | 0.21 (0.11–0.47) | 0.25 (0.10–0.41) | 0.568* |
Pain Intensity | |||||
∆ VAS, N (%) | |||||
≤ 2 | 46 (54.12) | 15 (62.50) | 20 (50.00) | 6 (46.15) | 0.533** |
≥ 2 | 39 (45.88) | 9 (37.50) | 20 (50.00) | 7 (53.85) | |
Time tot (hours) | |||||
mean (95% CI) | 140.43 (126.81–154.05) | 166.87 (143.42–190.33) | 133.67 (111.87–155.46) | 116.61 (87.64–145.59) | 0.042*** |
median (interquartile range) | 133.00 (99.00–192.00) | 190.50 (139.25–199.00) | 130.00 (96.00–185.50) | 120.00 (76.00–144.00) | |
Side effects, N (%)a | |||||
Gastrointestinalb | 23 (26.44) | 8 (33.33) | 9 (21.43) | 3 (23.08) | 0.553** |
CNSc | 10 (11.49) | 2 (8.33) | 4 (9.52) | 2 (15.38) | 0.780** |
Totald | 32 (36.78) | 10 (41.67) | 14 (33.33) | 4 (30.77) | 0.736** |
Morphine | |||||
Dose (mg/kg) | |||||
Dose24h | |||||
mean (95% CI) | 0.49 (0.45–0.53) | 0.55 (0.44–0.66) | 0.47 (0.41–0.52) | 0.49 (0.38–0.60) | |
median (interquartile range) | 0.46 (0.41–0.57) | 0.50 (0.43–0.65) | 0.46 (0.40–0.55) | 0.46 (0.43–0.60) | 0.170* |
Dosetot | |||||
mean (95% CI) | 3.19 (2.72–3.67) | 4.39 (3.49–5.30) | 2.75 (2.14–3.35) | 3.04 (1.48–4.60) | |
median (interquartile range) | 2.93 (1.82–4.42) | 4.52 (3.25) | 2.23 (1.72–3.40) | 2.98 (1.70–3.33) | 0.050* |
DoseVAS = 0 | |||||
mean (95% CI) | 0.54 (0.35–0.74) | 0.88 (0.28–1.49) | 0.41 (0.25–0.56) | 0.56 (0.00–1.16) | |
median (interquartile range) | 0.36 (0.17–0.60) | 0.54 (0.36–0.96) | 0.26 (0.14–0.52) | 0.37 (0.20–0.48) | 0.257* |
Pain Intensity | |||||
∆ VAS, N (%) | |||||
≤ 2 | 29 (49.15) | 10 (62.50) | 16 (51.61) | 2 (25.00) | 0.221** |
≥ 2 | 30 (50.85) | 6 (37.50) | 15 (48.39) | 6 (75.00) | |
Time tot (hours) | |||||
mean (95% CI) | 147.96 (131.56–164.36) | 174.62 (149.82–199.43) | 139.53 (113.56–165.50) | 134.00 (96.72–171.28) | 0.154*** |
median (interquartile range) | 142.50 (101.50–193.50) | 190.50 (150.00–199.00) | 130.25 (100.5–188.75) | 123.50 (99.50–173.25) | |
Side effects, N (%)a | |||||
Gastrointestinalb | 14 (23.33) | 5 (31.25) | 6 (18.75) | 2 (25.00) | 0.621** |
CNSc | 6 (10.00) | 1 (6.25) | 2 (6.25) | 1 (12.50) | 0.817** |
Totald | 19 (31.67) | 6 (37.57) | 9 (28.13) | 2 (25.00) | 0.752** |
N (%) ORa (95% CI) | |||
---|---|---|---|
G/G | A/G | A/A | |
Dose (mg/kg) | |||
High Dose24h (≥0.41 vs < 0.41) | 12 (50.00) vs 12 (50.00) | 21 (52.50) vs 19 (47.50) | 7 (53.85) vs 6 (46.15) |
1 (reference) | 0.66 (0.19–2.25) | 0.80 (0.16–4.01) | |
High Dosetot (≥2.18 vs < 2.18) | 16 (66.67) vs 8 (33.33) | 18 (42.86) vs 24 (57.14) | 7 (53.85) vs 6 (46.15) |
1 (reference) | 0.27 (0.08–0.87) | 0.42 (0.09–1.98) | |
High DoseVAS = 0 (≥0.26 vs < 0.26) | 14 (58.33) vs 10 (41.67) | 26 (65.00) vs 14 (35.00) | 9 (69.23) vs 4 (30.77) |
1 (reference) | 0.98 (0.30–3.24) | 1.47 (0.29–7.40) | |
Pain Intensity | |||
High ∆VAS (≥2 vs < 2) | 14 (58.33) vs 10 (41.67) | 20 (47.62) vs 22 (52.38) | 6 (46.15) vs 7 (53.85) |
1 (reference) | 0.51 (0.15–1.65) | 0.57 (0.12–2.82) | |
High Timetot (≥133 vs < 133) | 19 (79.17) vs 5 (20.83) | 19 (45.24) vs 23 (54.76) | 4 (30.77) vs 9 (69.23) |
1 (reference) | 0.18 (0.05–0.63) | 0.11 (0.02–0.56) | |
Side effects, N (%) | |||
Gastrointestinalb | 8 (33.33) vs 16 (66.67) | 9 (21.43) vs 33 (78.57) | 3 (23.08) vs 10 (76.92) |
1 (reference) | 0.56 (0.16–1.91) | 0.46 (0.09–2.44) | |
CNSc | 2 (8.33) vs 22 (91.67) | 4 (9.52) vs 38 (90.48) | 2 (15.38) vs 11 (84.62) |
1 (reference) | 1.39 (0.21–9.44) | 1.62 (0.17–15.78) | |
Totald | 10 (58.33) vs 10 (41.67) | 14 (33.33) vs 28 (66.67) | 4 (30.77) vs 9 (69.23) |
1 (reference) | 0.86 (0.29–2.56) | 0.58 (0.13–2.54) |
Systematic literature review
Study selection
Study quality assessment
Study description
Study name, [ref] | Study design | Patients characteristics | Opioid administered | Data | M/F | Mean Age (years) | ||
---|---|---|---|---|---|---|---|---|
Opioid dose | Pain | Side effects | ||||||
EPOS study | European observational study | Cancer pain patients | Morphine, methadone, fentanyl, hydromprphone, buprenorphine, ketobemidone, oxycodone | |||||
[18] (Klepstad, 2011) | 2201 Caucasians | X | 1154/1047 | 62.4 | ||||
[19] (Barratt, 2014)a | 667 subjects treated with transdermal fentanyl | 334/342 | Median: 64 | |||||
[20] (Barratt, 2015)b | 468 Caucasian subjects treated with transdermal fentanyl | X | X | 218/250 | Median: 64 | |||
[21] (Laugsand, 2011) | 1579 subjects not receiving chemotherapy and with information on nausea and vomiting | X | 850/729 | 61.9 | ||||
[22] Matsuoka, 2012 | Japanese observational study | 48 Opioid-treatment-naïve cancer patients | Morphine | X | 25/23 | 69.0 | ||
Norwegian observational study | 207 Cancer pain Caucasian patients | Morphine | X | X | X | 117/90 | 63.2 | |
[28] Ross, 2008 | United Kingdom case-control study | 228 Cancer pain patients | Morphine, Oxycodone, fentanyl, methadone | X | X | 106/122 | 57.2 | |
[26] Chatti, 2016 | Tunisian observational study | 129 Cancer pain patients | Morphine | X | 63/66 | Number of patients for each age group: 17-25 yrs.: 12 26-45 yrs.: 50 46-65 yrs.: 67 |
Study name [ref] | Variable | Genotype frequency (N, %) | Results (type of measure) |
p-value
|
---|---|---|---|---|
EPOS study [18] (Klepstad, 2011) | Dose in mg after 24 h | G/G (324, 22.18) A/G (726, 49.69) A/A (411, 28.13) | 180 mg 180 mg 160 mg (median) | 0.545 |
[22] Matsuoka, 2012 | Dose in mg after 24 h | G/G (19, 46.34) A/G (18, 43.90) A/A (4, 9.76) | 43.7 ± 21.4 28.9 ± 3.2 30.0 ± 0.0 (mean ± SD) | 0.03 |
[23] Rakvåg, 2005 | Dose in mg after 24 h | G/G (44, 21.25) A/G (96, 46.38) A/A (67, 32.37) | 155 ± 160 117 ± 100 95 ± 99 (mean ± SD) | 0.025 |
[26] Chatti, 2016 | Total dose requirement (continuous) AvsG | G/G (30, 23.3) A/G (57, 44.2) A/A (42, 32.6) | −2.10 (difference) | 0.334 |
Need of escalation (yes/no) AvsG | OR 0.76 (0.45; 1.27) | 0.293 |
Study name [ref] | Variable | Genotype frequency (N, %) | Results (type of measure) |
p-value
|
---|---|---|---|---|
EPOS study [20] (Barratt, 2015) | Brief Pain Inventory | G/G (109, 23.59) A/G (243, 52.60) A/A (110, 23.80) | Not reported | |
[23] Rakvåg, 2005 | Brief Pain Inventory after 24 h | G/G (44, 21.25) A/G (96, 46.38) A/A (67, 32.37) | 3.9 ± 2.2 3.7 ± 2.6 3.5 ± 2.3 (mean ± SD) | > 0.05 |
[28] Ross, 2008 | Brief Pain Inventory after 24 h | G/G (46, 20.81) A/G (119, 53.85) A/A (56, 25.34) | Not reported | 0.897 |
Study name [ref] | Variable | Genotype frequency (N, %) | Results (type of measure) |
p-value
|
---|---|---|---|---|
EPOS study [20] (Barratt, 2015) | Tiredness, Depression, Cognitive Dysfunction, Constipation | G/G (109, 23.59) A/G (243, 52.60) A/A (110, 23.80) | Not reported | |
[21] (Laugsand, 2011) | Nausea and Vomiting EORTC Score | G/G (341, 21.93) A/G (787, 50.61) A/A (427, 27.46) | 25.8 ± 30.5 21.5 ± 26.6 26.2 ± 29.2 (mean ± SD) | 0.002 |
[23] Rakvåg, 2005 | Fatigue EORTC Score | G/G (44, 21.25) A/G (96, 46.38) A/A (67, 32.37) | 73 ± 23 62 ± 24 66 ± 22 (mean ± SD) | > 0.05 |
Nausea and vomiting EORTC Score | 30 ± 27 24 ± 26 29 ± 27 (mean ± SD) | > 0.05 | ||
Dyspnea EORTC Score | 39 ± 35 38 ± 34 32 ± 33 (mean ± SD) | > 0.05 | ||
Sleep EORTC Score | 39 ± 35 38 ± 34 32 ± 33 (mean ± SD) | > 0.05 | ||
Appetite EORTC Score | 64 ± 36 49 ± 38 53 ± 38 (mean ± SD) | > 0.05 | ||
Constipation EORTC Score | 56 ± 41 57 ± 37 54 ± 37 (mean ± SD) | > 0.05 | ||
[28] Ross, 2008 | Central side effect | G/G (46, 20.81) A/G (119, 53.85) A/A (56, 25.34) | Not reported | 0.956 |