Background
Methods
Literature search
Data extraction
Results
Somatic pain
Study | Objectives | Reported pain as part of phenotype | Method and sample size | Source of CGRP | Results | Duration of the investigated condition | Correlation between CGRP level and pain |
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Alpar, 2002 [1] | Determine plasma CGRP in patients with whiplash injury who were treated by carpal tunnel decompression | Chronic shoulder and neck pain due to whiplash injury | 38 patients and 11 controls. Enzyme-immunoassay kit was used to measure the plasma CGRP | Blood (plasma) | Mean plasma levels was higher in patients, 400 ng/l, than in controls, 85 ng/l. Plasma levels were reduced, 65 ng/l, after carpal tunnel decompression | NR | Reduced plasma CGRP after the operation correlated to the pain reduction |
Bjur, 2005 [2] | Investigate innervation patterns of Achilles tendon in tendinosis tendon, and normal tendon | Chronic pain in tendinosis | Tissue samples from 21 patients and 9 controls | Tissue biopsies (Achilles tendon) | Inconclusive. CGRP was found in both patients and controls. The amount of CGRP-fibers was not quantified | Mean 19 months | NR |
Brown, 1997 [3] | Determine density of CGRP containing sensory nerve fibers in vertebral endplate in patients with degenerative disc disease | Severe back pain with or without sciatica in degenerative disc disease | Tissue from the intervertebral discs from 15 patients undergoing anterior lumbar discectomy and 7 healthy post-mortem controls | Tissue biopsies (intervertebral discs) | Marked increase in CGRP-containing sensory nerve fibers compared with controls | NR | NR |
Carlsson, 2006 [4] | Evaluate possible effects of acupuncture on sensory nerve fibers in human skin | Cervicobrachial pain, cervicocranial pain, hip pain and finger pain from arthrosis | Punch skin biopsies taken from 6 patients one week before acupuncture and 3–6 days after the 10th treatment | Tissue biopsies (skin) | The mean number of CGRP-IR nerve fibers were reduced after treatment | 4 months - >10 years | NR |
Danielson, 2008 [5] | Investigate CGRP prevalence in patients with tendinitis surgery. | Chronic painful patellar tendinosis | Patellar tendon biopsy in 7 patients | Tissue biopsies (patellar tendon) | CGRP rarely detected at perivascular sites | Chronic pain | NR |
Dong, 2015 [6] | Examine CGRP concentrations in patients with primary knee OA and controls | Chronic knee pain from OA | Serum CGRP concentrations in OA patients (n = 65) and controls (n = 21). | Blood (serum) | CGRP levels were higher in patients, 2.43 ng/mL, than in controls, 1.95 ng/mL | NR | CGRP concentrations in serum were correlated with pain intensity |
Ikeuchi, 2012 [7] | Determine sensory innervation of posterior cruciate ligament (PCL) in patients with OA | Chronic knee pain from OA | PCL samples from 10 patients and 5 pain-free controls with anterior cruciate ligament (ACL) rupture | Tissue biopsies (joint ligament) | No difference between patients and controls | NR | NR |
Jonhagen, 2006 [8] | Determine CGRP in human skeletal muscle at rest and after painful eccentric exercise | Experimental muscle pain after eccentric exercise | Microdialysis catheter inserted in quadriceps muscle in 8 healthy volunteers. Samples taken before and after exercise. | Blood (plasma) | CGRP levels were higher 2 days after exercise, 5.4 fmol/ml, than directly after exercise, 4.85 fmol/ml | VAS-score was assessed on the entry day (VAS = 0), day 1 (VAS = 1) and day 3 (VAS = 2) after the exercise | CGRP concentrations was positively correlated with pain intensity (VAS) |
Larsson, 1991 [9] | Investigate CGRP-levels from patients with rheumatoid arthritis and patients with meniscal/cruciate ligament injuries | Acute knee pain in meniscal/cruciate ligament injuries | Synovial fluid from the knee joint of 18 patients and 13 pain-free controls with ligament injuries | Synovial fluid (knee joint) | Increased CGRP levels in patients compared to controls. | 4-27 years | NR |
Lin, 2015 [10] | Investigate associations between plasma CGRP-levels and clinical outcome from APA, in patients with osteoarthritis and spinal stenosis | Chronic lower back pain (CLBP) in patients with osteoarthritis and spinal stenosis | Blood samples from 32 patients (APA-group) and 29 controls (sham APA-group). Samples were taken at baseline and 4 weeks later. VAS-score before treatment was 4. | Blood (plasma) | Patients showed a decrease in CGRP levels after treatment. No decrease in the control group | At least 3 months | 56% of the patient group reported a reduction in pain, whereas only 9% controls reported a reduction |
Lindh, 1999 [11] | Determine CGRP-LI levels in CSF in patients with chronic pain | Osteoarthritis, herniated lumbar disc and hip fracture pain | Sample: CSF Subjects: 35 patients (14 had knee or hip pain, 11 had rhizopathic pain due to herniated lumbar pain, 10 had pain from hip fracture and 12 healthy controls. Pain assessment: VAS | CSF | Decreased CGRP-LI levels were observed in patients compared to healthy controls | Osteoarthritis patients: >6 months. Rhizopathic pain: At least 1 month (1–13). Hip fracture pain: Up to 48 h | No correlation between CGRP-LI levels and VAS-values could be observed for any of the subjects participating in the study |
Onuoha, 1999 [12] | Investigate CGRP levels in patients with soft tissue injury | Acute muscle and ligament pain due to injury | Plasma CGRP-concentrations in 17 patients and 15 healthy controls | Blood (Plasma) | CGRP-levels were significantly higher in patients than controls | Up to 24 h | NR |
Ozawa, 2006 [13] | To determine sensory fibers innervating human degenerated lumbar intervertebral discs | Discogenic low back pain | Lumbar intervertebral disc was harvested from 8 patients, and immunostained for CGRP | Tissue biopsies (intervertebral disc) | CGRP-IR nerve fibers were observed in 6 out of 8 patients | NR | NR |
Samuelsson, 1993 [14] | Determine CSF CGRP levels in cancer patients | Cancer pain | CSF from 10 patients compared with 10 controls | CSF | No difference in CGRP-levels between patients and controls | NR | No difference between patients with pain and controls |
Sasaki, 2013 [15] | Investigate innervation patterns of ECRB in patients with recalcitrant tennis elbow | Lateral epicondylitis | Tissue biopsies from 8 patients and 2 controls. The control group suffered from osteochondritis | Tissue biopsies (lateral epicondyle) | A decrease in the immunorectivity of CGRP compared to controls | Mean duration 23 months | The innervation pattern did not appear to be correlated with VAS-score |
Sato, 2004 [16] | Elucidate expression of CGRP in temporomandibular joint (TMJ) from patients with internal derangement | TMJ pain | Synovial fluid from 48 patients and 7 controls, who had pain-free habitual dislocation | Synovial fluid (TMJ) | Increased CGRP in patients compared to controls | Mean duration 6 months | Positive correlation between the extent score of CGRP-levels and joint pain |
Saxler, 2007 [17] | Determine presence of CGRP-immunopositive nerve fibers in patients with OA | Hip pain from OA | Soft tissue biopsies from fossa acetabuli in 3 patients and 6 pain-free controls. 3 controls had a failed THA and 3 controls had femoral neck fractures | Tissue biopsies (fossa acetabuli) | Increased CGRP-LI in patients compared to controls. | NR | Positive correlation between CGRP and pain |
Takeshita, 2012 [18] | Clarify sensory innervation and inflammatory cytokines in OA patients | Severe hip pain from OA | Synovium from 50 patients and 12 controls with femoral neck fracture | Synovial fluid (hip) | CGRP-IR sensory nerve fibers were observed in 54% of the patients and 0% in controls | NR | NR |
Takeuchi, 2007 [19] | Determine CGRP’s role in patients with lumbar disc herniation, before and after lumbar discectomy | Sciatic pain/lumbar disc herniation | Plasma CGRP was measured in 27 patient before and 3 weeks after lumbar discectomy | Blood (plasma) | Plasma CGRP-levels were reduced after lumbar discectomy | 3 weeks | Reduced plasma CGRP after the operation correlated to lower VAS-levels |
Wang, 2015 [20] | Explore mechanisms of possible involvement and regulation of CGRP in pathological and inflammatory processes of arthritis in patients with developmental dysplasia of the hip (DDH) | Hip pain from OA | Synovial tissue samples from 67 patients: 35 with moderate DDH and 32 patients with severe DDH. 15 controls with traumatic femoral fracture | Synovial tissue (fossa acetabuli) | Increased CGRP in synovium fluid from patients in the severe DDH group compared to the moderate DDH group and controls | NR | The highest amount of CGRP correlated with the highest VAS |
Visceral pain
Study | Objectives | Reported pain as part of phenotype | Method and sample size | Source of CGRP | Results | Duration of the investigated condition | Correlation between CGRP level and pain |
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Arellano, 2011[1] | Investigate nerve growth factor role in development of pelvic pain in patients with endometriosis | Pain from endometriosis | Peritoneal fluids from 65 patients, 54 with pain, 11 without pain. 22 controls, where 12 reported pelvic pain | Peritoneal fluid | CGRP-neurite outgrowth was seen in patients | NR | The CGRP-neurite outgrowth did not correlate with pain symptoms |
Büchler, 1992 [2] | Identify characteristics of peptidergic innervation in patients with chronic pancreatitis | Pain from chronic pancreatitis | Pancreatic tissue from 20 patients compared to 10 organ donors | Tissue biopsies (pancreatic tissue) | CGRP-immunostaining was intensified in patients | NR | NR |
Mönnikes, 2005 [3] | Assess whether functional dyspepsia (FD) patients have altered mucosal CGRP concentrations | Pain from functional dyspepsia | Gastric mucosal biopsies from 13 patients and 18 controls. Biopsies were taken during gastric distention | Tissue biopsies (gastric mucosa) | No difference in CGRP-levels between patients and controls | The gastric distention took up to 80 min | A negative correlation between CGRP concentrations and pain was observed in patients. No such correlation was found in controls |
Tokushige, 2006 [4] | Determine the nerve fibers in patients with peritoneal endometriosis | Pain from endometriosis | Peritoneal endometriotic tissue from 40 patients and 36 healthy controls. Also 9 specimens from endosalpingiosis lesions were prepared | Tissue biopsies (endometriotic tissue) | Increase of CGRP-nerve fibers in patients, compared to controls and endosalpingiosis lesions | NR | NR |
Tokushige, 2007 [5] | Investigate types of nerve fibers in endometrium and myometrium in women with endometriosis | Pain from endometriosis | Tissue biopsies from 10 patients and 35 controls. All tissue biopsies were taken during hysterectomy | Tissue biopsies (endometriotic tissue) | Increased nerve fiber densities compared to controls | NR | NR |
Tympanidis, 2003 [6] | Evaluate nerve fiber density and pattern in patients with vulvodynia | Pain from vulvodynia | Biopsies from the wall of the vulval vestibule from 12 patients and 8 controls | Tissue biopsies (vulval vestibule) | No difference in CGRP-immunostaining between patients and controls | NR | NR |
Währborg, 1999 [7] | Clarify potential involvement of CGRP in anginal pain and myocardial ischemia in humans | Chest pain from angina and acute myocardial infarction | Plasma from 87 patients with AMI compared to 14 patients with severe angina pectoris | Blood (plasma) | No difference in CGRP-levels between patients with AMI and angina pectoris | At least 15 min | No correlation between CGRP-levels and pain |
Yoshida, 2013 [8] | Estimate expression of CGRP in esophageal mucosa in nonerosive reflux disease (NERD) patients | Pain due to NERD | Biopsies from 24 patients, compared to 24 controls | Tissue biopsies (esophageal mucosa) | No difference in CGRP-levels between patients and controls | NR | NR |
Inflammatory pain
Study | Objectives | Reported pain as part of phenotype | Method and sample size | Source of CGRP | Results | Duration of the investigated condition | Correlation between CGRP level and pain |
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Geber, 2007 [1] | Evaluate pain, hyperalgesia and neurosecretory function in pain models with CAP and ES | Experimental pain: CAP and ES | Samples from dermal microdialysis taken from 10 healthy volunteers. Patients rated pain levels after CAP and ES stimulation | Blood (plasma) | CGRP increase was measured after CAP, not after ES | 2 h | NR |
Hamed, 2011 [2] | Determine cutaneous innervation in burn patients with chronic pain | Chronic inflammatory skin pain | Skin biopsies from 12 patients and 33 controls suffering from unilateral injury, without pain | Tissue biopsies (skin) | Increase in CGRP density compared to controls | >24 months | CGRP-levels were higher in patients with pain compared to controls |
Krämer, 2005 [3] | Explore effect of specific blockers of NEP (phosphoramidon) and ACE (captopril) on intensity of neurogenic inflammation | Experimental pain: ES | Samples from dermal microdialysis were taken from 8 healthy volunteers. Patients quantified pain sensation during electrical stimulation using VAS | Dermal microdialysis | CGRP release could be measured after phosphoramidon perfusion | 1 h | CGRP release did not correlate to pain ratings during phosphoramidon infusion |
Kwak, 2014 [4] | Evaluate CGRP’s effect on wound healing process in hypertrophic scar formation | Inflammatory pain in scars | Skin biopsies from 43 patients. Biopsies were taken from scars, and also from a normal skin area | Tissue biopsies (skin) | Increased CGRP-levels in scars compared to matched unburned skin | >12 months | Increased CGRP-levels in painful scar areas compared to normal skin |
Onuoha, 2001 [5] | Examine plasma CGRP levels in patients with burns | Inflammatory pain from burn | Plasma was obtained from 13 patients immediately on hospital admission and 24 h after admission. 13 volunteers served as controls | Blood (plasma) | CGRP levels were higher on admission, 4.9 pmol/L and after 24 h, 7.3 pmol/L, than in controls, 1.9 pmol/L | NR | NR |
Salomon, 2008 [6] | Evaluate CGRP-levels in AD patients during exacerbation and disease remission | Pruritus due to AD | Plasma from 49 patients and 32 healthy controls | Blood (plasma) | CGRP-levels were lower compared to healthy controls | Mean 20.75 years (1-55years) | High CGRP concentrations correlated with severe pruritus |
Schmelz, 1997 [7] | Examine neuropeptide release in human skin elicited by histamine iontopheresis and topical CAP application | Experimental pain: histamine iontopheresis and CAP application | Samples from dermal microdialysis taken from 10 healthy volunteers. Patients were pain free prior start | Dermal microdialysis | CGRP concentration increased after histamine iontophoresis, but not capsaicin application | 3 h | NR |
Simone, 1998 [8] | Determine whether hyperalgesia after intradermal injection of CAP could be attributed to morphological changes in ENF’s | Experimental pain: intradermal CAP injection | Skin biopsies from 8 healthy volunteers | Tissue biopsies (skin) | Complete loss of CGRP-fibers was observed 72 h after capsaicin injections. They reappeared 3–4 weeks after | 6 weeks | NR |
Neuropathic pain
Study | Objectives | Reported pain as part of phenotype | Method and sample size | Source of CGRP | Results | Duration of the investigated condition | Correlation between CGRP level and pain |
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Albrecht, 2006 [1] | Investigate CGRP expression in skin from amputated extremity affected by CRPS | CRPS after amputation in upper and lower limbs | Skin tissue from 2 patients and 5 controls | Tissue biopsies (skin) | Loss of CGRP expression in CRPS patients | NR | NR |
Attal, 2016 [2] | Determine CGRP levels in peripheral neuropathic pain patients after treatment with botulinum toxin A | Peripheral neuropathic pain, mixed group | ELISA of biopsy from 23 patients with active treatment and 17 patients with placebo treatment at week 1 and 4 after study start | Skin | No change in CGRP levels at week 4 compared to week 1. Average pain score was not changed either | NR | None |
Awawdeh, 2002 [3] | Investigate presence of CGRP in the gingival crevicular fluid of teeth diagnosed with pain of pulpal origin | Tooth pain | Gingival crevicular fluid from a painful and non-painful site from 54 patients undergoing pulpectomy. 1 week after fluid was collected from 21 patients | Gingival crevicular fluid | No difference in CGRP-levels between painful tooth compared to the contralateral control tooth | NR | No clear association between CGRP-levels and dental pain |
Boras, 2010 [4] | Determine saliva and serum CGRP levels in patients with BMS | Burning mouth syndrome | Saliva and serum from 26 patients and 22 controls | Saliva and serum | No difference between patients and controls | NR | NR |
Birklein, 2001 [5] | Test contribution of neuropeptide release to pathophysiology of CRPS | CRPS in upper or lower limbs | Serum CGRP concentrations were measured in 19 patients on the affected (n = 19) side and non-affected side (n = 13) before and 9 months after therapy (n = 9). Comparison with controls (n = 16) | Blood (serum) | Increased CGRP levels in CRPS patients. No difference in CGRP levels in blood taken from affected versus non-affected side. After therapy – normalization of CGRP levels compared to healthy controls | Mean 29 weeks (range: 2 to 188 weeks) | No correlation between CGRP-levels and pain |
Chavarría-Bolanos, 2014 [6] | Determine CGRP-levels in dental pulp tissue samples from 8 patients subjected to undergo controlled orthodontic intrusive forces | Tooth pain | Human premolar dental pulp tissue was extracted from 8 patients, and 8 controls | Tissue biopsies (dental pulp) | No differences in CGRP levels between the two groups | 24 h | NR |
Hou, 2011 [7] | Determine whether CGRP-IL is increased among epidermal keratinocytes in PHN and diabetes | PHN and small fiber neuropathy | Punch biopsies from 5 patients with PHN from painful areas, 5 patients with diabetes (biopsies from feet) and 11 controls | Tissue biopsies (skin) | Increased CGRP-levels in keratinocytes from PHN patients compared to controls | NR | CGRP levels were higher in painful skin areas compared to non-painful locations |
Kalliomäki, 2011 [8] | Investigate structural and functional differences between patients with and without chronic pain following nerve injury | Hand pain due to nerve injury | Skin biopsies from 21 patients with pain and 9 controls without pain. All participants required hand surgery | Tissue biopsies (skin) | No difference in CGRP-staining between patients and controls | >1 year | No significant difference between pain and non-pain patients |
Lindqvist. 2000 [9] | Examine CGRP expression in painful Morton’s neuroma patients | Forefoot Morton’s neuroma | 11 nerve biopsies from 8 patients and 4 controls | Nerve biopsies | Increased levels of CGRP-IR nerve fibers compared to controls | NR | NR |
Schinkel, 2009 [10] | Compare systemic inflammatory mediators in patients with CRPS I with controls | CRPS in the upper limb | Blood samples were obtained from 22 patients. 12 patients had chronic CRPS and 10 patients had acute CRPS. Patients were compared to 8 controls | Blood (plasma) | CGRP-levels were lower in chronic CRPS patients, compared to controls | Acute: < 6 months Chronic: > 6 months | NR |
Zidverc-Trajkovic, 2009 [11] | Determine saliva CGRP levels in patients with BMS | Burning mouth syndrome | Saliva from 78 patients and 16 healthy controls | Saliva | Inconclusive, CGRP levels were non-significantly decreased in comparison to controls | At least 6 months | NR |