Chronic postsurgical inguinal pain: incidence and diagnostic biomarkers from a large German national claims database

Abstract

Background: Chronic postsurgical inguinal pain (CPIP) is the most common complication of groin hernia surgery. The characteristics of patients, their medical care, and choice of diagnostic tools remain to be defined to optimise preventive and therapeutic interventions.

Methods: Claims data from 2018 and a 1-yr follow-up were analysed for incidence and medical care. A separate cohort (141 healthy controls and 17 CPIP patients) was examined by deep phenotyping. This included sensory testing, blood and skin biopsies, MRI of the dorsal root ganglion (DRG), and patient-reported outcomes.

Results: Of 11,221 patients with hernia surgery in 2018 identified, 8.5% had pain before that was relieved by surgery, but a similar percentage had novel pain in this region. Deep phenotyping of 141 healthy controls provided a map of the inguinal sensory system. The following analysis of patients with CPIP revealed that they suffered from moderate pain with neuropathic features, individual sensory abnormalities, and unilateral L1 DRG atrophy. In the blood, levels of C-C-motif chemokine ligand (CCL2) and brain-derived neurotrophic factor (BDNF) were upregulated, whereas apolipoprotein A1 (ApoA1) concentration was reduced. A cluster of DRG atrophy, BDNF, ApoA1, and anxiety correlated best with the diagnosis. CPIP patients with novel pain had significantly more DRG atrophy (-24% ipsilateral vs contralateral volume).

Conclusions: CPIP is often newly acquired after surgery. A combination of DRG imaging, serum markers, and anxiety screening can support the diagnosis. In the future, this could guide clinicians towards more personalised therapies (e.g. targeting anxiety or lipid profiles) and possible altered surgical techniques.

Clinical trial registration: German Trial Registry DRKS00024588 and DRKS00016790.

Keywords: chronic postsurgical pain; cytokines; dorsal root ganglion; hernia surgery; imaging; lipids.

Fig 1

Incidence of ‘probable CPIP’ after hernia surgery and treatment with nonopioids. Patients from a major German health insurance undergoing hernia repair in 2018 were classified by pain before and after hernia surgery using surrogate pain codes from the ICD-10. (a) Percentage of patients categorised in pain 0/0 (no pain after surgery); pain 1/0 (only pain before surgery = pain resolution); pain 1/1 (pain before and after surgery = pain persistence); and pain 0/1 (pain only after surgery = novel pain). The latter two are labelled ‘probable CPIP’, because CPIP was not coded in the database. Proportion of patients in ‘probable CPIP’ subgroups receiving nonopioids, antineuropathic medication (anticonvulsants and antidepressants), or weak (WHO II) and strong (WHO III) opioids (b), specialised inpatient and outpatient pain therapy (c), physiotherapy and occupational therapy (d), suffering from psychiatric comorbidities (e), and undergoing psychotherapeutic treatment (f). n=11 221. CPIP, chronic postsurgical inguinal pain.

Fig 2

In quantitative sensory testing (QST), pressure pain in the groin was age- and sex-dependent. Healthy controls underwent QST of the groin and skin biopsy. (a) Cold detection threshold; (b) warm detection threshold; (c) thermal sensory limit; (d) cold pain threshold; (e) heat pain threshold; (f) mechanical detection threshold; (g) mechanical pain threshold; (h) mechanical pain sensitivity; (i) wind-up ratio; (j) vibration detection threshold; and (k) pressure pain threshold. (l) Normal values of intraepidermal nerve fibre density (IENFD). Skin punch biopsies were labelled with anti-PGP9.5. Representative examples with few (m) and many (n) fibres depicted. IENFD, intraepidermal nerve fibre density. (a–n) Data are shown by age groups in males and females and presented as median, 25th and 75th percentiles on linear y-axes. (a–k) n=141; N:n=104. One-way anova on ranks (Kruskal–Wallis test). Star symbols depict significant effects of age within one sex, hashtags show significant gender effects within one age group as follows: ∗^/#P<0.05; ∗∗^/##P<0.01; ∗∗∗^/###P<0.001; ∗∗∗∗^/####P<0.0001.

Fig 3

Unaltered sensory profiles and skin innervation in CPIP patients with ipsilateral L1 DRG atrophy. (a) Patients with CPIP from the cross-sectional study underwent deep phenotyping including QST, skin punch biopsies in the groin area, halfway between the iliac spine and the superior ramus of the public bone, and MRI neurography. (b) Sensory fibres were labelled with PGP9.5 to calculate intraepidermal nerve fibre density (IENFD) on the ipsilateral and contralateral sides. Ipsilateral (c) and contralateral (d) sensory thresholds. Dotted lines depict two standard deviations. (e) Fraction of CPIP patients with mechanical allodynia. (f–h) Axial T2-weighted MRI of the groin and bilateral DRG L1 after right-sided hernia repair. (f) Postoperative changes at the level of the inguinal canal (dotted red line) and the adjacent mesh. (g) Comparison of DRG level L1 of a patient with CPIP on the left side (ipsilateral DRG; red) compared with the contralateral unaffected DRG (white). (h) Evaluation of the DRG volumes of the inguinal dermatome of ipsilateral and contralateral groin (L1). Wilcoxon test; ∗∗∗P=0.0002 (n=17 of these 13 MRI and 11 skin biopsy). CDT, cold detection threshold; CPIP, chronic postsurgical inguinal pain; CPT, cold pain threshold; DRG, dorsal root ganglion; HPT, heat pain threshold; MDT, mechanical detection threshold; MPS, mechanical pain sensitivity; MPT, mechanical pain threshold; QST, quantitative sensory testing; TSL, thermal sensory limit; VDT, vibration detection threshold; WDT, warm detection threshold; WUR, wind-up ratio.

Fig 4

Increase in C-C-motif chemokine ligand (CCL2) and brain-derived neurotrophic factor (BDNF) levels but decrease in HDL and apolipoprotein A1 (ApoA1) levels in chronic postsurgical inguinal pain (CPIP). Nine blood cytokines, chemokines, lipid profiles, and two neuronal markers were measured in patients with CPIP and compared with age- and sex-matched controls. (a) CCL2; (b) HDL; (c) ApoA1; (d) neurofilament light chain (NfL); and (e) BDNF levels in the serum. n=15–17, t-test or Whitney–Mann test, with Bonferroni correction for multiple testing. ∗∗P<0.05, ∗∗∗P<0.001, ns=not significant.

Fig 5

Diagnostic tools and different pathophysiology depending on the presurgical pain. (a) Comparison of the DRG volume level L1 between patients with and without presurgical pain. (b) Mean decrease in impurity was used to compute the most relevant factors. (c) Summary of suggested diagnostic tools. n=11, t-test. ∗∗P<0.05. ApoA1, apolipoprotein A1; BDNF, brain-derived neurotrophic factor; contra, contralateral; DRG, dorsal root ganglion; ipsi, ipsilateral; Pre-OP, preoperative; STAI-T, State trait anxiety inventory - trait; CCL2, CC-chemokine ligeand 2; IENFD, intraepidermal nerve fibre density; TSL, thermal sensory limen; CPT, cold pain threshold; HPT, heat pain threshold; IL-4, interleukin-4; IL-6. interleukin-6; BDI-II, Beck Depression Index-II; TNF-a, Tumour necrosis factor alpha.