Table 1:
Descriptions of surgical cohorts, chronic post-surgical pain outcome definitions and STREGA/Q-Genie quality assessment scores for the studies evaluated in the systematic review
| Author | Year | Study design | Incidence of CPSP | N | Surgery | Female (/%) | Age | Race | Measures assessed and CPSP Outcome definition and time frame | Genes studied | Strega score | Q-Genie score** |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean (SD) | ||||||||||||
| Sia | 2010 | Prospective | 7.60% | 620 | Caesarian section | 100% | 18–45 | Han Chinese | Scar pain 3 and 6 months after
surgery CPSP Outcome: Persistent scar pain at 6 months after surgery |
ABCB1 | 23 | 52 (NC) |
| Costigan | 2010 | Prospective | NR | 151 | lumbar discectomy | NR | NR | Caucasian (Maine) | Baseline, 2, 6 and 12 months after
surgery; area-under-the-curve score for every pain variable was
converted these to a z-score by comparing the patient with the rest of
the cohort. CPSP outcome: mean of the four z-scores. RR defined. |
KCNS1 | 24 | 58 (NC) |
| 199 | Limb amputation | NR | NR | Israeli Jews | ||||||||
| 100 | amputees | 34% | 59 | Danish | ||||||||
| 529 | post-mastectomy | 100% | 52.9 | Israeli Jews | ||||||||
| Nissenbaum | 2010 | Retrospective | 72.60% | 549 | Breast cancer surgery | 100% | 52.9 | Ashkenazi and non-ashkenazi jews | CPSP outcome: Presence of pain at last 6 months (average 6.6 years) after surgery | CACGN2 | 21 | 64 (C) |
| Hickey | 2011 | Retrospective | 43% | 42 | Breast reconstruction | 100% | 36.6 (9.7) | NR | CPSP outcome: Pain attributed to breast surgery over a 6 year period | COMT, GCH1 | 20 | 59 (C) |
| Lee | 2011 | Prospective | NR | 98 | Molar tooth extraction | NR | NR | Caucasian/Irish | Highest VAS pain at rest in the postoperative
week, the highest VAS pain on movement in the postoperative week, days
until no analgesia was required and total PoSSe score. CPSP Outcome: Pain score 3 months after surgery |
COMT/GCH1 | 22 | 48 (NC) |
| Sorge | 2012 | Retrospective | 50% | 354 | Mastectomy | 100% | NR | NR | CPSP Outcome Intensity of a typical pain episode at least 6 months after surgery | P2RX7 | 19 | 46 (C) |
| Hegarty | 2012 | Prospective | 37.70% | Lumbar discectomy | European | Pain at 3 month follow up: CPSP Outcome: not at least a 70% reduction in the VAS pain intensity at 3 months compared to preoperative VAS on movement | GCH1, OPRM1, CYP2D6 | 20 | 53 (NC) | |||
| 20 | Pain cases | 55% | 40 | |||||||||
| 32 | Controls | 44% | 39 | |||||||||
| Lebe | 2013 | Retrospective | 30.40% | 275 | Lumbar disc surgery | 42% | 49.7(13.0) | NR | CPSP Outcome: pain, depression, physical functioning, disability 6 months after surgery | 5HTR1A, 5HTR2A | 19 | 57 (C) |
| Kolesnikov | 2013 | Prospective | 34.30% | 102 | Abdominal/radical prostatectomy/hysterectomy | 44% | 53.9 (9.8) | Caucasian | CPSP Outcome: Pain 3 months after surgery | OPRM1, GCH1 | 21 | 45 (NC) |
| Dominguez | 2013 | Case-control retrospective | 24% | 189 | Inguinal hernia | 56% | NR | Swedish | CPSP Outcome: Pain 6 months after surgery | HLA-DRB1 | 25 | 65 (C) |
| 231 | replication | NR | ||||||||||
| 436 | control | NR | ||||||||||
| Stephens | 2014 | Prospective | 11.60% | 172 (46/126) | Breast cancer surgery | 100% | Control: 58.6 (11.4); Cases: 52.4 (9.4) | Diverse | CPSP Outcome: persistent pain to no pain trajectory 6 months after surgery | IFNG, IL1R2, NFKB1, TNFA | 25 | 63 (NC) |
| Rut | 2014 | Prospective | 39.50% | 176 | Lumbar discectomy | 41% | 46.7 (13.2) | Caucasian | CPSP Outcome: Back pain and disability index 12 months after surgery | COMT | 20 | 55 (NC) |
| Liu | 2015 | .Prospective | 21.40% | 1152 | Vascular, thoracic, orthopedic, general, urologic, gynecologic, neuro/spine surgery | 52% | NR | Chinese | CPSP Outcome: Surgical site pain at 12 months after surgery | CTSG | 19 | 62 (NC) |
| Belfer | 2015 | Prospective | 12.80% | 429 | Herniotomy | 0% | 55.1 (13.3) | Caucasian (Danish/German) | CPSP Outcome: moderate-to-severe pain-related activity impairment 6 months postoperatively (Activity Assessment Scale≥8.3) | COMT, GCH1 | 25 | 60 (NC) |
| Montes | 2015 | Prospective | 18% | 2929 | Multiple cohorts (in all) | 26% | Hispanic | Primary CPSP Outcome: Pain 4 months after surgery. Secondary: CPSP at 12 and 24 months after surgery | 90 genes: DRD2, ATXN1, NFKBIA OPRD1, GRIK3, FAAH/NSUN4, Unknown, PTGS2, IL19/IL10, POMC,SCN9A, GABRA4, GABRB1, SLC6A3/CLPTM1L, GABRB2/GABRA6, GABRA1/LOC100287123, ATXN1, TNF/LTA, OPRM1, OPRK1, PENK, TRPA1, BDNFOS, BDNF, KIF18A/BDNF, DRD2,TMPRS S5/DRD2, “Unknown gene*, SLCO1B3, SLCO1A2, NFKBIA, SAMD4A/GCH1, GCH1, WDHD1, SLC6A2, TRPV1, CCDC55, SLC6A4, MC4R/LOC728115, B9D2/TGFB1, COMT, MAOA | 27 | 73 (C) | |
| 13.60% | 1761 | inguinal hernia | 60 (39–76) | |||||||||
| 11.80% | 416 | vaginal hysterectomy | 63 (45.7–76) | |||||||||
| 25.10% | 350 | abdominal hysterectomy | 48 (41–63.8) | |||||||||
| 37.60% | 402 | thoracotomy | 64 (49–76) | |||||||||
| Wieskopf | 2015 | prospective | 46.60% | 429 | herniotomy | 0% | 55.1 (13.3) | Caucasian | CPSP Outcome: Moderate/severe pain 6 months after surgery; To derive a single composite value representing pain of the head and neck, seven individual responses (duration of facial pain, intensity of current facial pain, intensity of greatest pain in the last 6 months, intensity of average pain over the last 6 months, primary headache characteristics, percentage of lifetime suffering from primary headache, and count of comorbid pain conditions) were normalized by conversion to z scores and then summed | CHRNA6 | 23 | 58 (NC) |
| 159 | replication (TMJ) | 100% | 36.8 | |||||||||
| Langford | 2015 | Prospective longitudinal | 27% | 398 | Breast cancer surgery | 100% | Controls 58.6 (11.4), Cases 53.4 (11.5) | Diverse | CPSP Outcome: Latent classes of pain 6 months after surgery (No Pain, Mild Pain, Moderate Pain, Severe Pain) | KCND2, KCNJ3, KCNJ6, KCNK9, KCNA1, KCND2, KCNS1, KCNJ3, KCNJ6, KCNK3, KCNK9 | 23 | 60 (NC) |
| Thomazeau | 2016 | Prospective | 28.80% | 104 | Knee replacement | 0% | 69 (9.0) | NR | CPSP Outcome: NRS score ≥ 1/10 over 8 days, 6 months after surgery. | OPRM1, GCH1 | 24 | 53 (NC) |
| George | 2016 | Prospective | NR | 150 | Arthroscopic shoulder surgery | 34% | 42.7 (16.4) | 85% Caucasian; diverse | Brief Pain Inventory (BPI) Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire 3, 6 and 12 months postoperative: CPSP Outcome: 12 month pain intensity outcome | ADRB2, OPRM1, AVPR1A, GCH1, KCNS1, IL1B, IL6, TNF/LTA | 27 | 61 (NC) |
| Kalliomaki | 2016 | Retrospective | NA | 91 | Hernia cases | Swedish | Inguinal pain questionnaire was
used to assess pain. Neuropathic pain was defined as persisting pain in
combination with sensory disturbance CPSP Outcome: pain of grade 3 (i.e.pain that could not be ignored but did not interfere with everyday activities) over the past week. Mean time since surgery was 49.1 months (SD 23.1 months) |
OPRM1 TNF-, GRIK3, GCH1, BDNF CACNA2D2 | 22 | 60 (C) | ||
| Pain cases | 91% | 58 (14.6) | ||||||||||
| 93 | Controls | 94% | 57.7 (14.8) | |||||||||
| Warner | 2017 | Retrospective | NR | 613 (discovery) 212 and 908 (replication) | Total joint replacement | NR | NR | United Kingdom/Netherlands | CPSP Outcome: Neuropathic pain (painDETECT score >12) – no time specified | PRKCA | 25 | 60 (C) |
NR: Not reported; NA: Not applicable; PoSse: VAS: Visual analog scale
Studies included in the meta-analysis are highlighted in gray color.
Gene names: COMT (catechol-O-methyltransferase); GCH1 (GTP cyclohydrolase 1); OPRM1 (opioid receptor mu 1); ABCB1 (ATP binding cassette subfamily B member 1); ADRB2 (adrenoceptor beta 2); AVPR1A (arginine vasopressin receptor 1A); TNF (tumor necrosis factor); LTA (lymphotoxin alpha); IL6 (interleukin 6); IL1R1 (interleukin 1 receptor type 1); IL1R2 (interleukin 1 receptor type 2); IL4 (interleukin 4); IL10 (interleukin 10); IL13 (interleukin 13); NFKB1 (nuclear factor kappa B subunit 1); HLA-DRB1 (major histocompatibility complex, class II, DR beta 1); PRKCA (protein kinase C alpha); CDH18 (cadherin 18); TG (thyroglobulin); OPRD1 (opioid receptor delta 1); GRIK3 (glutamate ionotropic receptor kainate type subunit 3); FAAH (fatty acid amide hydrolase); NSUN4 (NOP2/Sun RNA methyltransferase family member 4); PTGS2 (prostaglandin-endoperoxide synthase 2); IL19 (interleukin 19); POMC (proopiomelanocortin); SCN9A (sodium voltage-gated channel alpha subunit 9); GABRA4 (gamma-aminobutyric acid type A receptor alpha4 subunit); GABRB1 (gamma-aminobutyric acid type A receptor beta1 subunit); SLC6A3 (solute carrier family 6 member 3); CLPTM1L (CLPTM1 like); GABRB2 (gamma-aminobutyric acid type A receptor beta2 subunit); GABRA6 (gamma-aminobutyric acid type A receptor alpha6 subunit); GABRA1 (gamma-aminobutyric acid type A receptor alpha1 subunit); ATXN1 (ataxin 1); OPRK1 (opioid receptor kappa 1); PENK (proenkephalin); TRPA1 (transient receptor potential cation channel subfamily A member 1); BDNF (brain derived neurotrophic factor); KIF18A (kinesin family member 18A); DRD2 (dopamine receptor D2); TMPRSS5 (transmembrane serine protease 5); SLCO1B3 (solute carrier organic anion transporter family member 1B3); SLCO1A2 (solute carrier organic anion transporter family member 1A2); NFKBIA (NFKB inhibitor alpha); SAMD4A (sterile alpha motif domain containing 4A); WDHD1 (WD repeat and HMG-box DNA binding protein 1); SLC6A2 (solute carrier family 6 member 2); TRPV1 (transient receptor potential cation channel subfamily V member 1); SLC6A4 (solute carrier family 6 member 4); MC4R (melanocortin 4 receptor); B9D2 (B9 domain containing 2); TGFB1 (transforming growth factor beta 1); MAOA (monoamine oxidase A); CHRNA6 (cholinergic receptor nicotinic alpha 6 subunit); KCND2 (potassium voltage-gated channel subfamily D member 2); KCNJ3 (potassium voltage-gated channel subfamily J member 3); KCNJ6 (potassium voltage-gated channel subfamily J member 6); KCNK9 (potassium two pore domain channel subfamily K member 9); KCNA1 (potassium voltage-gated channel subfamily A member 1); KCNS1 (potassium voltage-gated channel modifier subfamily S member 1); KCNK3 (potassium two pore domain channel subfamily K member 3); CACNG2 (calcium voltage-gated channel auxiliary subunit gamma 2); PoSse: Postoperative symptom severity score; HADS = Hospital Anxiety and Depression Score
Strega score:
Q-Genie scores: For studies with control groups (C) Scores ≤35 indicate poor quality studies, >35 and ≤45 indicate studies of moderate quality, and >45 indicate good quality studies.
For studies without control groups (NC): Scores ≤32 indicate poor quality studies, >32 and ≤40 indicate studies of moderate quality, and >40 indicate good quality studies.