Highlights
- •Phantom and residual limb pain were assessed in 122 double limb amputees.
- •High intraindividual concordance between limbs was observed for each type of pain.
- •Phantom and residual pain were only moderately associated.
- •Intraindividual concordance suggested a predisposition for both types of pain.
- •Medium association between both types of pain suggested some distinct risk factors.
Abstract
Most, but not all, limb amputees develop phantom limb pain (PLP) or residual limb
pain (RLP), and large interindividual differences in pain intensity and course are
apparent. The present cross-sectional study of 122 double amputees investigated the
possible role of genetic factors in PLP and RLP, assuming that strong individual predisposition
results in high intraindividual concordance in pain phenotype. Intraindividual concordance
was observed in 116 (95%) patients for development of PLP and in 110 patients (90%)
for development of RLP. For both pain types, high intraindividual concordance was
also observed for remission and current intensity. Moderate association for lifetime
history and current intensity of PLP and RLP was observed both within and between
limbs. The high intraindividual concordance in pain phenotypes suggests strong individual
predisposition for PLP and RLP development. However, the finding of only moderate
association between PLP and RLP suggests that susceptibility to these pain phenomena
involves distinct, as well as common, risk factors. Genome-wide studies in large samples
of single amputees may facilitate the dissection of these phenotypes and their underlying
mechanisms.
Perspective
The observation of high intraindividual concordance for PLP and RLP in 122 double
amputees suggests that individual factors contribute to post-amputation pain. The
relatively low intraindividual association between PLP and RLP suggests that these
factors are at least partially specific for each pain type.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of PainAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects.Bull World Health Organ. 2001; 79: 373
- Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity.Brain. 2012; 135: 404-417
- Post-amputation pain is associated with the recall of an impaired body representation in dreams-results from a nation-wide survey on limb amputees.PLoS One. 2015; 10: e0119552
- Nature and nurture of human pain.Scientifica. 2013; 2013
- Surgically-induced neuropathic pain (SNPP): understanding the perioperative process.Ann Surg. 2013; 257: 403
- Factors associated with phantom limb pain: a 31/2-year prospective study.Clin Rehabil. 2010; 24: 444-453
- Is revision surgery following lower-limb amputation a worthwhile procedure? A retrospective review of 71 cases.Injury. 2011; 42: 660-666
- Brain plasticity and intellectual ability are influenced by shared genes.J Neurosci. 2010; 30: 5519-5524
- The prevalence of chronic chest and leg pain following cardiac surgery: a historical cohort study.Pain. 2003; 104: 265-273
- Genetic and environmental influences on coping styles: a twin study.Psychosom Med. 1999; 61: 469-475
- Phantom limb pain after amputation in diabetic patients does not differ from that after amputation in nondiabetic patients.Pain. 2013; 154: 729-732
- Evidence for heritability of pain in patients with traumatic neuropathy.Pain. 2004; 108 (author reply 202): 200-201
- Heritability of symptoms in the neuroma model of neuropathic pain: replication and complementation analysis.Pain. 2005; 116: 294-301
- Pain1: a neuropathic pain QTL on mouse chromosome 15 in a C3HxC58 backcross.Pain. 2005; 116: 289-293
- Phantom pain and risk factors: a multivariate analysis.J Pain Symptom Manage. 2002; 24: 578-585
- Phantom pain, residual limb pain, and back pain in amputees: results of a national survey.Arch Phys Med Rehabil. 2005; 86: 1910-1919
- Replication and meta-analysis of common variants identifies a genome-wide significant locus in migraine.Eur J Neurol. 2013; 20: 765-772
- Phantom limb pain: a case of maladaptive CNS plasticity?.Nat Rev Neurosci. 2006; 7: 873-881
- Phantom limb pain after lower limb trauma: origins and treatments.Int J Low Extrem Wounds. 2011; 10: 224-235
- Psychological aspects of pain.Ann Agric Environ Med. 2013; (Spec no. 1): 23-27
- Stability of phantom limb phenomena after upper limb amputation: a longitudinal study.Neuroscience. 2008; 156: 939-949
- Phantom limb, phantom pain and stump pain in amputees during the first 6 months following limb amputation.Pain. 1983; 17: 243-256
- Environmental influences on neural plasticity, the limbic system, emotional development and attachment: a review.Child Psychiatry Hum Dev. 1999; 29: 189-208
- Psychophysiological contributions to phantom limbs.Can J Psychiatry. 1992; 37: 282-298
- Persistent postsurgical pain: risk factors and prevention.Lancet. 2006; 367: 1618-1625
- Schmerz. 2009; 23: 479-488
- Phantom pain and phantom sensations in upper limb amputees: an epidemiological study.Pain. 2000; 87: 33-41
- Twin studies of posttraumatic stress disorder: differentiating vulnerability factors from sequelae.Neuropharmacology. 2012; 62: 647-653
- Pain in traumatic upper limb amputees in Sierra Leone.Pain. 2002; 99: 309-312
- Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood.Bioinformatics. 2012; 28: 2540-2542
- Early life adversity as a risk factor for fibromyalgia in later life.Pain Res Treat. 2012; 2012: 140832
- A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain.Eur J Pain. 2015; 19: 392-399
- Plasticity in human motor cortex is in part genetically determined.J Physiol. 2011; 589: 297-306
- Pain genetics: past, present and future.Trends Genet. 2012; 28: 258-266
- Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception.Pain. 1999; 80: 67-82
- Twin studies of pain.Clin Genet. 2012; 82: 331-340
- Individual differences in pain sensitivity: genetic and environmental contributions.Pain. 2008; 136: 21-29
- The influence of preamputation pain on postamputation stump and phantom pain.Pain. 1997; 72: 393-405
- Genome-wide association study identifies a potent locus associated with human opioid sensitivity.Mol Psychiatry. 2014; 19: 55-62
- pain2: A neuropathic pain QTL identified on rat chromosome 2.Pain. 2008; 135: 92-97
- Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region.Ann Rheum Dis. 2013; 72: 427-436
- Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.Nature. 2009; 460: 748-752
- Autotomy following limb denervation: effects of previous exposure to neurectomy.Pain. 1985; 21: 105-115
- Nothing in pain makes sense except in the light of genetics.Pain. 2014; 155: 841-842
- Mapping a gene for neuropathic pain-related behavior following peripheral neurectomy in the mouse.Pain. 2001; 93: 101-106
- Chronic phantom and stump pain among American veterans: results of a survey.Pain. 1984; 18: 83-95
- Epidemiology of neuropathic pain and its impact on quality of life.Curr Pain Headache Rep. 2012; 16: 191-198
- Neuropathic pain: redefinition and a grading system for clinical and research purposes.Neurology. 2008; 70: 1630-1635
- The role of psychological factors in chronic pain.Acta Anaesthesiol Scand. 1999; 43: 885-888
- Five-factor personality traits and pain sensitivity: a twin study.Pain. 2013; 154: 722-728
- Ein strukturiertes Interview zur Erfassung von Phantom- und Stumpfphänomenen nach Amputation.Der Schmerz. 2001; 15 ([in German]): 172-178
- Heritability of nociception IV: neuropathic pain assays are genetically distinct across methods of peripheral nerve injury.Pain. 2014; 155: 868-880
Article info
Publication history
Published online: September 29, 2015
Accepted:
August 27,
2015
Received in revised form:
July 13,
2015
Received:
March 22,
2015
Footnotes
F.S., R.B.-B., Z.S., H.F., and M.R. contributed equally to this work.
This research was supported by a European Research Council Advanced Grant for the project “Phantom Phenomena: A Window To The Mind And The Brain (PHANTOMIND),” which received research funding from the European Community's Seventh Framework Programme (FP7/2007–2013/ERC Grant Agreement No. 230249 [http://erc.europa.eu/]) awarded to H.F. and by funding from the German Research Foundation to the project “Genetische Grundlagen des Phantomschmerzes: Aufbau einer nationalen Forschungsressource (PHANTOMGENE)” (DFG; WU392/7-1: 2010–2014) awarded to S.W., H.F., and M.R. Z.S. is founding CEO and owner of Algogene Pain Genetics Inc, a board member of Newron Pharmaceuticals S.p.A., and received consultant fees from deCODE genetics. All other authors declare that they have no conflicts of interest regarding the material discussed in the article.
Supplementary data accompanying this article are available online at www.jpain.org and www.sciencedirect.com.
Identification
Copyright
© 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.
