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Table 1 Studies on the role of CGRP in somatic pain

From: Calcitonin gene-related peptide and pain: a systematic review

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
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
  1. APA Auricular point acupressure, CGRP Calcitonin gene-related peptide, CGRP-LI Calcitonin gene-related peptide-like immunoreactivity, CLBP Chronic low back pain, CRPS Complex regional pain syndrome, CSF Cerebrospinal fluid, ECRB Extensor carpi radialis brevis, KL grades Kellgreen and Lawrence classification, used to assess the severity of OA, NR not reported, OA Osteoarthritis, PHN Postherpetic neuralgia, THA Total hip arthroplasties