Effect of painless diabetic neuropathy on pressure pain hypersensitivity (hyperalgesia) after acute foot trauma

Abstract

Introduction and objective: Acute injury transiently lowers local mechanical pain thresholds at a limb. To elucidate the impact of painless (diabetic) neuropathy on this post-traumatic hyperalgesia, pressure pain perception thresholds after a skeletal foot trauma were studied in consecutive persons without and with neuropathy (i.e. history of foot ulcer or Charcot arthropathy).

Design and methods: A case-control study was done on 25 unselected clinical routine patients with acute unilateral foot trauma (cases: elective bone surgery; controls: sprain, toe fracture). Cases were 12 patients (11 diabetic subjects) with severe painless neuropathy and chronic foot pathology. Controls were 13 non-neuropathic persons. Over 1 week after the trauma, cutaneous pressure pain perception threshold (CPPPT) and deep pressure pain perception threshold (DPPPT) were measured repeatedly, adjacent to the injury and at the opposite foot (pinprick stimulators, Algometer II®).

Results: In the control group, post-traumatic DPPPT (but not CPPPT) at the injured foot was reduced by about 15-25%. In the case group, pre- and post-operative CPPPT and DPPPT were supranormal. Although DPPPT fell post-operatively by about 15-20%, it remained always higher than the post-traumatic DPPPT in the control group: over musculus abductor hallucis 615 kPa (kilopascal) versus 422 kPa, and over metatarsophalangeal joint 518 kPa versus 375 kPa (medians; case vs. control group); CPPPT did not decrease post-operatively.

Conclusion: Physiological nociception and post-traumatic hyperalgesia to pressure are diminished at the foot with severe painless (diabetic) neuropathy. A degree of post-traumatic hypersensitivity required to 'pull away' from any one, even innocuous, mechanical impact in order to avoid additional damage is, therefore, lacking.

CLINICAL RESEARCH ARTICLE

Effect of painless diabetic neuropathy on pressure pain hypersensitivity (hyperalgesia) after acute foot trauma

Tobias Wienemann, Dipl. Biol.1, Ernst A. Chantelau, MD, PhD1* and Armin Koller, MD2

1Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 2Interdisciplinary Diabetic Foot Centre, Mathias-Spital, Rheine, Germany

Abstract

Introduction and objective : Acute injury transiently lowers local mechanical pain thresholds at a limb. To elucidate the impact of painless (diabetic) neuropathy on this post-traumatic hyperalgesia, pressure pain perception thresholds after a skeletal foot trauma were studied in consecutive persons without and with neuropathy (i.e. history of foot ulcer or Charcot arthropathy).

Design and methods : A case-control study was done on 25 unselected clinical routine patients with acute unilateral foot trauma (cases: elective bone surgery; controls: sprain, toe fracture). Cases were 12 patients (11 diabetic subjects) with severe painless neuropathy and chronic foot pathology. Controls were 13 non-neuropathic persons. Over 1 week after the trauma, cutaneous pressure pain perception threshold (CPPPT) and deep pressure pain perception threshold (DPPPT) were measured repeatedly, adjacent to the injury and at the opposite foot (pinprick stimulators, Algometer II®).

Results : In the control group, post-traumatic DPPPT (but not CPPPT) at the injured foot was reduced by about 15-25%. In the case group, pre- and post-operative CPPPT and DPPPT were supranormal. Although DPPPT fell post-operatively by about 15-20%, it remained always higher than the post-traumatic DPPPT in the control group: over musculus abductor hallucis 615 kPa (kilopascal) versus 422 kPa, and over metatarsophalangeal joint 518 kPa versus 375 kPa (medians; case vs. control group); CPPPT did not decrease post-operatively.

Conclusion : Physiological nociception and post-traumatic hyperalgesia to pressure are diminished at the foot with severe painless (diabetic) neuropathy. A degree of post-traumatic hypersensitivity required to 'pull away' from any one, even innocuous, mechanical impact in order to avoid additional damage is, therefore, lacking.

Keywords: quantitative sensory testing; allodynia; neuropathy; neuropathic ulcer; neuropathic arthropathy; nociception

*Correspondence to: Ernst A. Chantelau, Heinrich-Heine-University, DE-40225 Düsseldorf, Germany, Email: [email protected]

Received: 14 May 2014; Revised: 17 September 2014; Accepted: 13 October 2014; Published: 6 November 2014

Diabetic Foot & Ankle 2014. © 2014 Tobias Wienemann et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Citation: Diabetic Foot & Ankle 2014, 5 : 24926 - http://dx.doi.org/10.3402/dfa.v5.24926

Experimental human and animal studies have addressed local nociception and pain perception around an acute injury. Mostly, acute injuries of a limb were studied, involving skin and/or skeletal structures. Clinical studies on mechanical ankle injuries (sprains) showed intense spontaneous pain and pain at activity immediately after injury, which normalised with healing over a period of 6-8 weeks (1). Correspondingly, deep pressure pain perception thresholds (DPPPT) to a blunt stimulus were acutely lowered at the injured limb, and normalised successively (2). Another clinical study found lowered pain threshold to punctuate stimuli in the inflamed area of an operated knee, but not in the adjacent non-inflamed area, in patients undergoing total knee arthroplasty (3). A recent experimental study in healthy volunteers showed lowered cutaneous pressure pain perception threshold (CPPPT) adjacent to an acute injury involving skin, subcutaneous tissue, muscle, and fascia (4).

Post-traumatic pain perception thresholds to punctuate and blunt stimuli are lowered in the area of an acute injury (4, 5), equivalent to primary hyperalgesia (increased sensitivity to noxious stimuli directly at the injured structures) and secondary hyperalgesia (increased sensitivity to noxious stimuli in uninjured tissues surrounding the site of injury). Hypersensitivity to innocuous stimuli (allodynia) may develop around an injury, contributing to evoked post-traumatic pain. Furthermore, there is spontaneous non-evoked post-traumatic local pain. All physiological post-traumatic pains are generated and mediated by toxic molecules, cytokines, inflammation factors, and neurogenic factors like substance P, calcitonin-gene-related peptide, and nerve growth factor (6-9) most of which are reduced in diabetic neuropathy.

Hyperalgesia is caused by peripheral sensitisation of nociceptors and by central sensitisation of the brain, whereas allodynia is caused by central sensitisation only. We recently reported cross-sectional data suggesting secondary hyperalgesia to punctuate cutaneous and blunt deep pressure stimulation adjacent to an acute foot injury in non-neuropathic subjects. By contrast, patients with severe painless diabetic neuropathy and an active penetrating foot ulcer failed to show the same hyperalgesia (10). To assess these observations in more detail deep pain thresholds to blunt pressure stimuli and cutaneous pain thresholds to punctuate 'pinprick' pressure stimuli were followed up after an acute injury of the foot skeleton in non-neuropathic subjects (controls), and in patients with severe painless neuropathy (cases).

Study design

A prospective observational case-control study was devised to follow up deep and cutaneous pressure hyperalgesia in the vicinity of an acute trauma of the foot skeleton. The follow-up design was adapted from a previous short-term longitudinal study on acute ankle sprain by Kerkhoffs et al. (11). Pressure pain and vibration perception thresholds were measured at both feet, the traumatised and the opposite one, and at both hands. To ensure reliability, all measurements were taken by one single examiner (T.W.) according to Nussbaum and Downes (12). The study was approved by the ethics committees of the medical faculties of the University of Münster/Germany, the Medizinische Hochschule Hannover/Germany, and the University of Erlangen-Nürnberg/Germany. All participants provided written informed consent.

Participants

In total 25 Caucasians aged 30-77 volunteered for the study, 10 women and 15 men. There were 13 consecutive subjects with acute foot or ankle trauma (control group), admitted to the emergency departments of the university hospitals in Hannover and Nürnberg. They were free from peripheral neuropathy and persistent foot pathology. The case group comprised 12 consecutive patients undergoing elective foot surgery at the Mathias-Spital in Rheine; all of them had severe painless neuropathy due to diabetes mellitus ( n =11), or alcohol abuse (n =1), and chronic foot pathology (e.g. osteomyelitis).

Inclusion criteria

Control subjects with foot casualty were eligible, if they had sustained but a singular foot or ankle trauma within the preceding 24 hours, and proved to have normal vibration sensation at the feet. Exclusion criteria were: trauma requiring immediate operation, open wound, age below 18 years, specific comorbidities (thrombocytopenia, bleeding disorders, capillary fragility, mental disorders, cancer, rheumatic arthritis, fever, complex regional pain syndrome, multiple sclerosis, stroke, all kinds of peripheral neuropathies - for example, from diabetes mellitus, alcohol abuse, vitamin B12 deficiency, hereditary neuropathy), and concurrent medication with anticoagulant, analgesic, or antidepressant drugs. Foot infection, for example, osteomyelitis or cellulitis, and foot ischaemia due to peripheral arterial disease were other exclusion criteria.

Case subjects were eligible, if they were to undergo elective foot surgery for chronic osteomyelitis or Charcot arthropathy, and proved to have peripheral painless sensory neuropathy of whatever origin. Exclusion criteria were age below 18, specific comorbidities (cellulitis, peripheral arterial disease, thrombocytopenia, bleeding disorders, capillary fragility, mental disorders, cancer, rheumatic arthritis, fever, complex regional pain syndrome, multiple sclerosis, stroke, advanced peripheral arterial disease), and concurrent use of anticoagulants. Demographic variables of cases and controls are summarised in Table 1.

[Table omitted -see PDF.]

Numerical rating scale 0-10. Median (95% CI). Spontaneous posttraumatic foot pain intensity: significant differences between control group day post 0 and case group day post 2 (p =0.0006), and controls day 6 vs. cases day 7 (p =0.03). Stimulated pain intensity at feet and hands: differences between control and case group on corresponding time points not statistically significant (n.s.). See Table 6. DPPPT=deep pressure pain perception threshold.

Discussion

The present data are in line with our previous cross-sectional data (10), where we had shown that subjects with severe painless neuropathy displayed higher mechanical pain thresholds at an injured foot as compared to non-neuropathic control subjects with acute foot injury. Pain thresholds at the hands were not different between the neuropathic and non-neuropathic subjects (10), consistent with the anatomical distribution of diabetic neuropathy (25, 26). Moreover, we had shown that the DPPPT at the injured foot was lower than at the opposite foot in the non-neuropathic controls - and that this phenomenon was not evident in the cases with neuropathy. However, in many cases with neuropathy, DPPPT (m. abductor hallucis) at the injured foot was within the normal range, while CPPPT (digital skinfold) was above the upper limit of measurement in all cases (10).

The present post-traumatic VPT, CPPPT, and DPPPT were in the same ranges as those reported earlier (10, 18, 22). What the present data adds is some information on the time course of post-traumatic changes of the perception thresholds. VPT did not react at all to the acute trauma, which is in line with previous reports (4). At the injured foot in the control group, DPPPT was decreased as compared to the opposite foot on the day of the trauma (and also as compared to the non-injured control subjects in our previous studies) (10). DPPPT decreased also at the opposite foot on day 3 after the trauma (suggesting central sensitisation) (6, 9). In the case group, DPPPT seemingly decreased by day 2 after the trauma (compared to the pre-traumatic DPPPT), however, at a much higher level than in the control group. This implies that case patients may have been lacking the protective withdrawal reflex produced by the physiologic post-traumatic hypersensitivity.

In the case group, plantar skin at a digital skinfold was probably completely pain-insensate (CPPPT above upper limit of measurement in 11 out of 12 subjects in the present study, no evidence of post-traumatic hyperalgesia), whereas deep pressure pain sensation and post-traumatic secondary hyperalgesia at the rear foot seemed to be partially preserved (DPPPT at m. abductor hallucis below upper limit of measurement in 6 out of 12 subjects). This finding, which is consistent with our previous data (10, 18, 22), remains to be explained. Skin pressure pain perception and deep pressure pain perception are generated independently from each other (27-29). Cutaneous pressure pain is sharp and pricking, transmitted by A-delta fibre nociceptors. Deep pressure pain is dull and aching and probably more of an extreme pressure-discomfort (30, 31), transmitted by various small-calibre afferents (7, 32, 33). However, the nature of the deep pressure pain, as produced percutaneously by Algometer II®, is generally not well understood. In the present case subjects, some of the intramuscular nociceptors/mechanoceptors inside m. abductor hallucis may have escaped neuropathic destruction, according to the distal-to-proximal gradient of neuropathy at the diabetic foot (34) (possibly also some intracutaneous nociceptors were preserved at the plantar arch, which remains to be demonstrated). Of these residual intramuscular nociceptors/mechanoceptors, some might have been captured and stimulated simultaneously by the relatively large contact area (1 cm2) compressed. This could have caused - via spatial summation (31) - a signal strong enough to enter the central nervous system.

The diminished mechanical pain thresholds at the controls' contralateral feet and at the ipsilateral and contralateral hands following the unilateral foot trauma may be due to central sensitisation (7). This phenomenon was not observed in the case subjects, possibly because painless peripheral neuropathy had reduced the nociceptive inflow to the brain that is required to produce central sensitisation.

The pain ratings in the case group, although in line with some of our previous data (22), are difficult to understand. Expectedly, intensity of spontaneous pain at rest in the traumatised foot was scored lower in the case group than in the control group, consistent with the painless neuropathy of the feet in the cases. Spontaneous non-evoked pain intensity was substantial in the controls and decreased appreciably some days after the trauma, whereas the DPPPT increased. This is consistent with previous reports (1-4). In the case group, non-evoked pain intensity was zero and did not change post-operatively. However, intensity of evoked pain felt at reaching the DPPPT was scored higher than in the control group, and higher at the hands than at the feet (albeit not statistically significant). The latter may suggest differences in pain history between controls and cases, with subsequent differences in interoceptive nociception and pain tolerance (35). Of note, two (particularly pain-intolerant) case patients were permanently on opioid analgesics. It may be assumed that the diabetic patients of the case group had particularly irregular pain feelings in their hands, for several reasons. First, because they are accustomed to pricking their fingertips several times per day for the purpose of blood glucose self-monitoring. Every finger prick felt, of course, is painful. Second, the difference in neuropathy between their feet and hands likely affects pain feelings in their hands, as the severely impaired sensation in the feet together with the preserved sensation in the hands produces a (kind of 'schizophrenic') discrepancy of pain feelings, perceptions, and emotions. Third, this deviation from normal has developed insidiously, and only after the normal pain memory became established with sensitivity still being equal at upper and lower limbs.

Our study's limitations are associated with the clinical setting. Due to limited resources, study groups were small, non-selected, and heterogeneous regarding age, body mass index (BMI), and male-to-female ratio. The controls had had no previous foot trauma, whereas the cases had suffered from chronic foot pathology and/or a prior history of painful neuropathy. It was impossible to clearly determine the zone around the foot injury that was not involved in the post-traumatic inflammation, that is, the zone of secondary hyperalgesia (9). Thus, we could not clearly differentiate between primary and secondary hyperalgesia. The CPPPT could have been affected by some inapparent skin hardness. In the control group, the pre-traumatic thresholds could not be measured, due to constraints of the study design. The decrease in DPPPT after trauma could have been superimposed by a learned behavioural response that may develop when deep pressure pain is measured once daily over several days (36). With pain threshold measurements, the normal range - that is the inter-subject variance - is large and the intra-subject repeatability may be poor (depending, amongst others, on the training of the examiner) (21, 37). All of these pitfalls and shortcomings in QST methodology and study design may have precluded statistical significance for many a group difference. Nevertheless, the data apparently support our previous hypothesis that abrogated cutaneous pressure pain perception might be more important than reduced deep pressure pain perception as a precondition for both types of neuropathic foot injuries (diabetic neuropathic ulcers or Charcot arthropathy) (10, 22, 34).

Conclusion

In patients with acute skeletal trauma of the foot, severe painless (diabetic) neuropathy minimised the post-traumatic hyperalgesia to pressure stimulation, the physiologic safeguard against further exposing an injured site to any mechanical impact (38, 39). Hence, these patients are devoid of protective withdrawal behaviour to escape an innocuous stimulus. More study is required to firmly establish the mechanisms by which painless diabetic neuropathy of various degrees impairs posttraumatic hyperalgesia and to discern the contributions of impaired deep versus cutaneous nociception to the clinical features of the diabetic foot.

Conflict of interest and funding

The authors have received no funding or benefits from industry to conduct this study.

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