Inflammation induces α1-adrenoceptor expression in peripheral blood mononuclear cells of patients with complex regional pain syndrome.

Persistent regional and systemic inflammation may promote pain and hyperalgesia in complex regional pain syndrome (CRPS). In this study, we investigated whether stimulation of α1-adrenoceptors (α1-AR) on peripheral blood mononuclear cells (PBMC) might contribute to this inflammatory state. PBMC were isolated from venous blood collected from 21 CRPS patients and 21 sex and age-matched controls. Lipopolysaccharide (LPS), a bacterial toxin, was administered to cultured PBMC for 24 h to trigger inflammation. Exposure to LPS resulted in heightened gene expression of α1-AR subtype B (α1B-AR) in PBMC of CRPS patients relative to controls. Interleukin (IL)-1ß and IL-6 levels did not change when the α1-AR agonist phenylephrine was administered to naïve PBMC. However, α1-AR stimulation following LPS treatment increased IL-6 mRNA and protein levels in PBMC of patients and controls. To investigate the possible consequence of heightened IL-6 levels on immunoglobulin G antibody production, PBMC were stimulated with CD40 ligand and IL-21 to generate plasmablasts (B cells that secrete antibodies). This response was similar in patients and controls. Adding IL-6 to the cell culture medium increased plasmablast differentiation in controls and antibody production both in patients and controls. These findings suggest that the inflammatory cascade associated with elevated levels of IL-6 may generate α1B-AR expression in CRPS PBMC. A reciprocal interaction between heightened α1-AR expression in PBMC and IL-6 secretion may contribute to systemic inflammation and antibody production in CRPS.

Olfaction in Complex Regional Pain Syndrome.

OBJECTIVE: Complex regional pain syndrome (CRPS) is associated with a range of sensory disturbances on the symptomatic side of the body but whether this includes olfaction is uncertain. To clarify this, the aims of this study were to compare ratings of intensity and hedonic appeal of household odorants in CRPS patients and controls, and to determine whether ratings differed between the symptomatic and contralateral sides within the sample of patients. METHODS: Six odorants (vanilla, fish sauce, vinegar, eucalyptus, almond essence and acetone) were presented sequentially in random order on cottonwool buds held in the midline approximately 1 cm from both nostrils in 37 CRPS patients and 21 pain-free controls. Each odor was rated for intensity and hedonic appeal, and participants reported whether the odor was stronger and/or smelt different on one side than the other. RESULTS: The odorants smelt worse for patients than controls (P < .05 for the symptomatic and contralateral sides) but neither the intensity nor the unpleasantness of the odorants was greater on the symptomatic than contralateral side in the group as-a-whole. CONCLUSIONS: These findings suggest that the trigeminal component of olfaction interacts bilaterally with pain-sensitized circuits in the thalamus or higher cortical centers to distort odor perception in patients with CRPS. This aberrant process appears to differ from the mechanism that underlies hemilateral hyperalgesia in other sensory modalities.

Auditory disturbances in patients with complex regional pain syndrome.

ABSTRACT: Complex regional pain syndrome (CRPS) is often associated with reduced sound tolerance (hyperacusis) on the affected side, but the mechanism of this symptom is unclear. As compensatory increases in central auditory activity after cochlear injury may trigger hyperacusis, hearing and discomfort thresholds to pure tones (250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz) were assessed in 34 patients with CRPS and 26 pain-free controls. In addition, in 31 patients and 17 controls, auditory-evoked potentials to click stimuli (0.08 ms duration, 6 Hz, 60 dB above the hearing threshold) were averaged across 2000 trials for each ear. Auditory discomfort thresholds were lower at several pitches on the CRPS-affected than contralateral side and lower at all pitches on the affected side than in controls. However, ipsilateral hyperacusis was not associated with psychophysical or physiological signs of cochlear damage. Instead, neural activity in the ipsilateral brainstem and midbrain was greater when repetitive click stimuli were presented on the affected than contralateral side and greater bilaterally than in controls. In addition, click-evoked potentials, reflecting thalamo-cortical signal transfer and early cortical processing, were greater contralaterally in patients than controls. Together, these findings suggest that hyperacusis originates in the ipsilateral brainstem and midbrain rather than the peripheral auditory apparatus of patients with CRPS. Failure of processes that jointly modulate afferent auditory signalling and pain (eg, inhibitory influences stemming from the locus coeruleus) could contribute to ipsilateral hyperacusis in CRPS.

Stimulation of alpha-1 adrenoceptors may intensify cutaneous inflammation in complex regional pain syndrome.

ABSTRACT: Alpha-1 adrenoceptors are overexpressed in the epidermis of a subgroup of patients with complex regional pain syndrome (CRPS). Activating α 1 -adrenoceptors in epidermal cells increases production of the proinflammatory cytokine interleukin-6 (IL-6), a mediator of inflammation. To investigate whether this might exacerbate inflammation in CRPS, primary keratinocytes or dermal fibroblasts were cultured from skin biopsies obtained from the affected limb of 25 patients and a similar site in 28 controls. The fundamental proinflammatory cytokine, tumor necrosis factor alpha, was administered for 24 hours to initiate inflammation. After this, cells were incubated for 6 hours with the α 1 -adrenoceptor agonist phenylephrine. Exposure to tumor necrosis factor alpha induced proinflammatory cytokine mRNA production and protein secretion in keratinocytes and fibroblasts and enhanced α 1B -adrenoceptor mRNA expression in keratinocytes. Additional stimulation of α 1 adrenoceptors with phenylephrine increased the production of IL-6 mRNA and protein secretion in both cell types. Under all conditions, gene and protein α 1 -adrenoceptor levels and cytokine gene expression and protein secretion were similar, overall, in patients and controls, except for abnormally high α 1 -adrenoceptor protein levels in the keratinocytes of 3 of 17 patients. These findings suggest that persistent inflammation in CRPS is not due to dysfunction of skin cells but is a normal response to extrinsic signals. After α 1 -adrenoceptor stimulation of keratinocytes, increases in IL-6 mRNA but not protein were proportional to basal α 1 -adrenoceptor protein levels. Skin cells play an important role in persistent inflammation in CRPS. Potentially, a positive feedback loop between α 1 -adrenoceptors and IL-6 production in skin cells contributes to this inflammatory state.

Co-morbidity between trigeminal autonomic cephalalgias and complex regional pain syndrome: Two case reports.

BACKGROUND: Trigeminal autonomic cephalalgias and complex regional pain syndrome are rare conditions, and their co-occurrence has not been reported previously.Clinical findings: In two patients, ipsilateral trigeminal autonomic cephalalgias developed after the onset of upper limb complex regional pain syndrome. Hyperalgesia to thermal and mechanical stimuli extended beyond the affected limb to encompass the ipsilateral forehead, and was accompanied by ipsilateral hyperacusis and photophobia. In addition, examination of the painful limb and bright light appeared to aggravate symptoms of trigeminal autonomic cephalalgias. Detailed examination of the association between facial and upper limb pain indicated that both sources of pain cycled together. Furthermore, in one case, stellate ganglion blockade inhibited pain for an extended period not only in the affected limb but also the face. CONCLUSIONS: These findings suggest some overlap in the pathophysiology of complex regional pain syndrome and trigeminal autonomic cephalalgias. Specifically, central sensitization and/or disruption of inhibitory pain modulation on the affected side of the body in complex regional pain syndrome might trigger ipsilateral cranial symptoms and increase vulnerability to trigeminal autonomic cephalalgias.

Pupillary Reflexes in Complex Regional Pain Syndrome: Asymmetry to Arousal Stimuli Suggests an Ipsilateral Locus Coeruleus Deficit.

Converging lines of evidence suggest that autonomic and nociceptive pathways linked with the locus coeruleus are disrupted in complex regional pain syndrome (CRPS). To investigate this, pupillary dilatation to arousal stimuli (which reflects neural activity in the locus coeruleus) and pupillary reflexes to light were assessed in a cross-sectional study of 33 patients with CRPS. Moderately painful electrical shocks were delivered to the affected or contralateral limb and unilateral 110 dB SPL acoustic startle stimuli were delivered via headphones. To determine whether the acoustic startle stimuli inhibited shock-induced pain, startle stimuli were also administered bilaterally 200 ms before or after the electric shock. The pupils constricted briskly and symmetrically to bright light (500 lux) and dilated symmetrically in dim light (5 lux). However, the pupil on the CRPS-affected side was smaller than the contralateral pupil before and after the delivery of painless and painful arousal stimuli. Auditory sensitivity was greater on the affected than unaffected side but acoustic startle stimuli failed to inhibit shock-induced pain. Together, these findings suggest that neural activity in pathways linked with the locus coeruleus is compromised on the affected side in patients with CRPS. This may contribute to autonomic disturbances, auditory discomfort and pain. PERSPECTIVE: The locus coeruleus is involved not only in modulation of pain but also regulates sensory traffic more broadly. Hence, fatigue of neural activity in the ipsilateral locus coeruleus might not only exacerbate pain and hyperalgesia in CRPS but could also contribute more generally to hemilateral disturbances in sensory processing.

Photophobia in complex regional pain syndrome: visual discomfort is greater on the affected than unaffected side.

ABSTRACT: In complex regional pain syndrome (CRPS), hyperalgesia encompasses uninjured sites on the ipsilateral side of the body and may also include the special senses because auditory discomfort often is greater on the CRPS-affected side. To determine whether this hemilateral hyperalgesia involves the visual system, the discomfort threshold to a light-source that increased in intensity at 100 lux/second from 500 to 3600 lux was investigated for each eye, and the nasal and temporal half of each visual field, in 33 patients with CRPS and 21 pain-free controls. Recent headache history was reviewed and, in patients with CRPS, sensitivity to mechanical and thermal stimuli was assessed in all 4 limbs and on each side of the forehead. In addition, the pupils were photographed in dim and bright light. The visual discomfort threshold was lower in patients than controls and was lower on the CRPS-affected than unaffected side (P < 0.001), indicating photophobia. Visual discomfort was unrelated to pupil diameter. Headache frequency was greater in CRPS patients than controls, and unilateral headaches were more likely to be on the CRPS-affected than contralateral side. Similarly, mechanical and thermal hyperalgesia was greater in the CRPS-affected than contralateral limb and was greater ipsilateral than contralateral to CRPS in the forehead and nonsymptomatic limbs. Ipsilateral photophobia was associated with mechanical and thermal hyperalgesia in the ipsilateral forehead but not the CRPS-affected limb. Together, these findings suggest that aberrant processing of nociceptive input in the ipsilateral trigeminal-medullary region of the brainstem contributes to visual discomfort in CRPS.

The Source of Hemisensory Disturbances in Complex Regional Pain Syndrome.

OBJECTIVES: In complex regional pain syndrome (CRPS), sensory deficits and/or hyperalgesia often extend beyond the affected limb to encompass other sites on the ipsilateral side of the body. The aim of this study was to determine whether hyperalgesia in the ipsilateral forehead reflects disinhibition and/or sensitization of trigeminal afferent or second-order neurons on the CRPS-affected side. PARTICIPANTS AND METHODS: To investigate this, blink reflexes to supraorbital electrical stimuli (a 2 mA triple pulse delivered using a concentric electrode) were recorded bilaterally in 30 CRPS patients and 20 controls of similar age and sex distribution. In addition, the effect of acoustic startle stimuli on pain and blink reflexes to supraorbital electrical stimuli was explored. RESULTS: Supraorbital electrical stimulation was more painful on the affected than unaffected side in patients (P<0.05), and was more painful on both sides in patients than controls (P<0.001). In addition, electrical stimulation of the ipsilateral forehead increased loudness and auditory discomfort to acoustic startle stimuli (P<0.05). However, blink reflexes were similar on both sides in patients, and smaller in amplitude and of longer latency in patients than controls (P<0.05). DISCUSSION: These findings suggest that trigeminal sensory nerve input activates sensitized and/or disinhibited nociceptive circuits in the thalamus or higher cortical centers in CRPS. This not only evokes ipsilateral supraorbital hyperalgesia but also compromises auditory perception. Hence, crosstalk between auditory and nociceptive signals at sites of convergence within the central nervous system may generate hyperacusis in CRPS.

Expression of Cutaneous Beta-2 Adrenoceptors Is Similar in Patients with Complex Regional Pain Syndrome and Pain-Free Controls.

OBJECTIVE: Studies in rodents suggest that cutaneous beta-2 adrenoceptors (ß2-ARs) mediate inflammation and pain after tissue injury and that inflammation and peripheral nerve injury trigger increases in neuronal ß2-AR expression. Hence, the aim of this study was to investigate the expression of ß2-ARs on keratinocytes and dermal nerves in patients with complex regional pain syndrome (CRPS). DESIGN, SETTING, AND SUBJECTS: Fifty-eight patients with CRPS were recruited for this study. In addition, skin biopsies were obtained from 13 pain-free women and three pain-free men of similar age and sex distribution as the patients. METHODS: Quantitative sensory tests for assessing sensitivity to pressure, pinprick, light touch, heat, and cold were administered, and skin biopsies were obtained from the affected and contralateral limbs. Skin biopsies were also obtained from a similar site on the dorsal hand or foot of pain-free controls. Immunohistochemistry and confocal microscopy were used to identify ß2-ARs on keratinocytes, dermal nerves, and blood vessels in the skin samples. RESULTS: The distribution of ß2-ARs in keratinocytes and nerves was similar in the affected and contralateral limbs of patients and was similar for target cells in patients and controls. However, elevated ß2-AR expression in reticular nerve bundles was associated with heightened sensitivity to heat pain. CONCLUSIONS: These findings do not support a major role of cutaneous ß2-ARs in CRPS. However, activation of neuronal ß2-ARs may contribute to thermal hyperalgesia in a subgroup of patients. Whether activation of ß2-ARs on keratinocytes mediates inflammation early in the course of CRPS requires further investigation.

Parallels between lumbosacral radiculopathy and complex regional pain syndrome: α1-adrenoceptor upregulation, reduced dermal nerve fibre density, and hemisensory disturbances in postsurgical sciatica.

Residual lower-limb pain after low back surgery (postsurgical sciatica) and complex regional pain syndrome (CRPS) involving a lower limb are separate conditions but may share some mechanisms (eg, tissue inflammation, neuroimmune disturbances, and central neuroplasticity). As adrenergically evoked pain contributes, in part, to CRPS, whether an adrenergic mechanism also contributes to postsurgical sciatica was investigated in this study. Immunohistochemistry was used to identify α1-adrenoceptors (α1-AR) on nerve fibres and other targets in the affected and contralateral skin of 25 patients with postsurgical sciatica, and α1-AR expression was investigated in relation to pain and pinprick hyperalgesia after intradermal injection of the α1-AR agonist phenylephrine. In addition, quantitative sensory testing was performed on all 4 limbs and on each side of the forehead. α1-AR expression was greater in keratinocytes (but not blood vessels or nerve fibres) in the symptomatic than contralateral leg, and dermal nerve fibre density was reduced in both legs. However, distal adrenergic involvement in pain in postsurgical sciatica seems unlikely, as neither heightened α1-AR expression in keratinocytes nor reduced dermal nerve fibre density were associated with pain or hyperalgesia to intradermal phenylephrine injection. Sensitivity to pressure-pain, pinprick, and cold-pain was greater in the ipsilateral than contralateral forehead of the entire cohort, but sensory disturbances were most pronounced in patients with additional CRPS-like features. Together, these findings suggest that bilateral distal neuropathy and central neuroplastic changes are involved not only in the pathophysiology of CRPS but also in postsurgical sciatica. This may have treatment implications for patients with postsurgical sciatica.

Complex regional pain syndrome: intradermal injection of phenylephrine evokes pain and hyperalgesia in a subgroup of patients with upregulated α1-adrenoceptors on dermal nerves.

The aim of this study was to determine whether upregulated cutaneous expression of α1-adrenoceptors (α1-AR) is a source of pain in patients with complex regional pain syndrome (CRPS). Immunohistochemistry was used to identify α1-AR on nerve fibres and other targets in the affected and contralateral skin of 90 patients, and in skin samples from 38 pain-free controls. The distribution of α1-AR was compared between patients and controls, and among subgroups of patients defined by CRPS duration, limb temperature asymmetry, and diagnostic subtype (CRPS I vs CRPS II). In addition, α1-AR expression was investigated in relation to pain and pinprick hyperalgesia evoked by intradermal injection of the α1-AR agonist phenylephrine. Expression of α1-AR on nerve bundles in the CRPS-affected limb was greater in patients who reported prolonged pain and pinprick hyperalgesia around the phenylephrine injection site than in patients with transient pain after the injection. In addition, α1-AR expression in nerve bundles was greater in patients with CRPS II than CRPS I, and was greater in acute than more long-standing CRPS. Although less clearly associated with the nociceptive effects of phenylephrine, α1-AR expression was greater on dermal nerve fibres in the painful than contralateral limb. Together, these findings are consistent with nociceptive involvement of cutaneous α1-AR in CRPS. This involvement may be greater in acute than chronic CRPS, and in CRPS II than CRPS I.

Dermal nerve fibre and mast cell density, and proximity of mast cells to nerve fibres in the skin of patients with complex regional pain syndrome.

An interaction between cutaneous nerves and mast cells may contribute to pain in complex regional pain syndrome (CRPS). To explore this, we investigated the density of dermal nerve fibres, and the density and proximity of mast cells to nerve fibres, in skin biopsies obtained from the affected and unaffected limbs of 57 patients with CRPS and 28 site-matched healthy controls. The percentage of the dermis stained by the pan-neuronal marker protein gene-product 9.5 was lower in the affected limb of patients than in controls (0.12 ± 0.01% vs 0.22 ± 0.04%, P < 0.05), indicating a reduction in dermal nerve fibre density. This parameter did not correlate with CRPS duration. However, it was lower in the affected than unaffected limb of patients with warm CRPS. Dermal mast cell numbers were similar in patients and controls, but the percentage of mast cells less than 5 µm from nerve fibres was significantly lower in the affected and unaffected limbs of patients than in controls (16.8 ± 1.7%, 16.5 ± 1.7%, and 31.4 ± 2.3% respectively, P < 0.05). We confirm previous findings of a mild neuropathy in CRPS. Our findings suggest that this either develops very early after injury or precedes CRPS onset. Loss of dermal nerve fibres in CRPS might result in loss of chemotactic signals, thus halting mast cell migration toward surviving nerve fibres. Failure of normal nerve fibre-mast cell interactions could contribute to the pathophysiology of CRPS.

Hemisensory disturbances in patients with complex regional pain syndrome.

Sensory disturbances often spread beyond the site of injury in complex regional pain syndrome (CRPS) but whether this applies equally to CRPS I and II, or changes across the course of the disease, is unknown. Establishing this is important, because different symptom profiles in CRPS I and II, or in acute vs chronic CRPS, might infer different pathophysiology and treatment approaches. To explore these questions, sensory disturbances were assessed in the limbs and forehead of 71 patients with CRPS I and 33 patients with CRPS II. Pain had persisted up to 12 months in 32 patients, for 13 to 36 months in 29 patients, and for longer than this in 43 patients. Patients with CRPS I were more likely to be female, and pain was more likely to be present in an additional limb, than patients with CRPS II. Conversely, pain was more likely to be associated with sensory deficits and allodynia in patients with CRPS II than CRPS I. Nevertheless, heightened sensitivity, allodynia, and/or hyperalgesia to mechanical and thermal stimuli were detected in a hemisensory distribution ipsilateral to the affected limb in both forms of CRPS. Some of these hemisensory disturbances strengthened with chronicity of pain. These findings suggest that heightened excitability of nociceptive pathways in CRPS spreads to hemisensory convergence points in the brainstem or higher brain centres, possibly in association with compromised pain controls. The similarity of symptom profiles in chronic CRPS I and II implies shared mechanisms despite different triggers.

Hyperacusis in chronic pain: neural interactions between the auditory and nociceptive systems.

OBJECTIVE: Sensory disturbances are common in chronic pain patients. Hyperacusis can be an especially debilitating experience. Here, we review published work on how the auditory and nociceptive systems might interact in chronic pain syndromes to produce pain-hyperacusis. DESIGN: Literature review. STUDY SAMPLE: The PubMed and Scopus databases were searched for relevant articles published between 2000 and 2017 using the primary search terms "hyperacusis"/"hyperacousis" and "pain". Ten papers were found using this strategy. Supplementary sources were identified by browsing textbooks and the reference lists of identified articles. RESULTS: The importance of central mechanisms in pain-hyperacusis was highlighted in the 10 selected papers. Hyperacusis is a significant but under-recognised symptom in conditions such as complex regional pain syndrome and fibromyalgia, and an integral feature of migraine. CONCLUSIONS: Nociceptive circuits become hypersensitive in acute and chronic pain; this sensitivity spreads from the periphery to spinal neurons and higher centres in the brain, leading to hyperalgesia or spontaneous pain even in the absence of peripheral nociceptive input. This "central sensitisation" may alter activity at sensory convergence points in the thalamus and brainstem centres such as the locus coeruleus, and give rise to hyperacusis in certain pain syndromes.

Topical prazosin attenuates sensitivity to tactile stimuli in patients with complex regional pain syndrome.

BACKGROUND: The sympathetic nervous system may play an important role in certain forms of chronic pain. The main aim of this study was to determine whether functional blockade of α1 -adrenoceptors would alter sensitivity to cutaneous stimulation in patients with complex regional pain syndrome (CRPS). METHODS AND RESULTS: In an initial study, high-performance liquid chromatography-mass spectrometry of intradermal interstitial fluid collected from the forearms of three healthy individuals established that the α1 -adrenoceptor antagonist prazosin penetrated the skin barrier when mixed in Lipoderm(®) cream base. Next, we found that application of this cream to the forearm of 10 healthy participants attenuated axon reflex vasodilatation to the iontophoresis of phenylephrine, demonstrating functional blockade of α1 -adrenoceptors. Subsequently, effects of the cream on sensitivity to mechanical and thermal stimulation were investigated in 14 healthy participants and 19 patients with CRPS (eight with an apparent adrenergic component of pain). Both in patients and controls, topical application of the prazosin cream increased sensitivity to skin cooling but reduced sensations evoked by gentle brushing. In addition, hyperalgesia to sharp stimulation was lower at the prazosin- than vehicle-treated site in the CRPS-affected limb, and allodynia to brushing was lower at the prazosin-treated than vehicle-treated site in patients with an adrenergic component of pain. CONCLUSIONS: Prazosin cream inhibited adrenergic axon reflex vasodilatation in healthy volunteers, and also inhibited dynamic allodynia and punctate hyperalgesia in the CRPS-affected limb of some patients. Further studies are required to assess the potential benefits of topically applied prazosin for CRPS.

Topical treatment in pain medicine: from ancient remedies to modern usage.

Over several millennia, substances have been applied to the skin for treatment of pain. Some ingredients are in current use; others have been discontinued. Mechanisms of action include interactions with nociceptive neural networks and inflammatory processes. Substances must penetrate the stratum corneum barrier and vehicles that enhance penetration have been developed. Topical drugs with links to the past include menthol, capsaicin, some opioids, local anesthetic agents and NSAIDs. Mandragora is also described as an example of a herbal remedy that has been discontinued due to its toxicity. The future for topical drugs is promising, with the advent of new drugs tailored for specific pain mechanisms and the development of both penetration enhancers and sterile preparation methods.

Up-regulation of cutaneous α1-adrenoceptors after a burn.

Stimulation of α1-adrenoceptors evokes inflammatory cytokine production, boosts neurogenic inflammation and pain, and influences cellular migration and proliferation. As expression of α1-adrenoceptors increases on dermal nerves and keratinocytes after peripheral nerve injury, the aim of this study was to determine whether another form of tissue injury (a cutaneous burn) triggered a similar response. In particular, changes in expression of α1-adrenoceptors were investigated on dermal nerve fibres, keratinocytes and fibroblast-like cells using immunohistochemistry 2-12 weeks after a full thickness burn in Wistar rats. Within two weeks of the burn, local increases in α1-adrenoceptor expression were seen in the re-forming epidermis, in dense bands of spindle-shaped cells in the upper dermis (putatively infiltrating immune cells and fibroblasts), and on nerve fibres in the deep dermis. In addition, nerve fibre density increased approximately three-fold in the deep dermis, and this response persisted for several more weeks. In contrast, α1-adrenoceptor labelled cells and staining intensity in the upper dermis decreased contralateral to the burn, as did nerve fibre density in the deep dermis. These findings suggest that inflammatory mediators and/or growth factors at the site of a burn trigger the synthesis of α1-adrenoceptors on resident epidermal cells and nerve fibres, and an influx of α1-adrenoceptor labelled cells. The heightened expression of α1-adrenoceptors in injured tissue could shape inflammatory and wound healing responses.

Effects of testosterone treatment on bone mineral density in hypogonadal men receiving intrathecal opioids.

BACKGROUND: Opioid induced depression of sex hormones is a common finding in chronic pain patients receiving long-term opioids by oral, parenteral and even intrathecal routes of administration. The hypothalamic suppression by opioids leads to a hypogonadal state with low testosterone levels in males and subsequent low bone mineral density (BMD). METHODS: We have studied the effects of intrathecally administered opioids on BMD in a group of male chronic pain patients. In addition, we have studied the effects of supplementary testosterone on bone metabolism to see if the adverse effects of intrathecal opioids can be reversed. RESULTS: Eleven of the 27 patients were on supplementary testosterone having previously been diagnosed as hypogonadal with low serum testosterone. Duration of testosterone supplementation was greater than 2 years in all 11 patients. Both serum total and free testosterone levels were higher in patients on supplementary testosterone than in patients who did not receive this treatment. Of the 16 patients not on testosterone supplement, 14 (87%) had low serum testosterone levels (<10 nmol/L) and 11 (69%) had low or osteoporotic T scores. Within this group, low free testosterone was associated with low BMD scores, and this persisted after correcting for age. Eight of the patients on testosterone supplement had normal BMDT scores and three (27%) had low or osteoporotic T scores. T and age-corrected BMDZ scores were significantly greater in the 11 patients on testosterone supplements than BMD scores in the other 16 patients. CONCLUSION: Testosterone supplementation was found to largely correct the effects of intrathecal opioids on testosterone levels and BMD.

Up-regulation of cutaneous α1 -adrenoceptors in complex regional pain syndrome type I.

BACKGROUND: In a small radioligand-binding study of cutaneous α1 -adrenoceptors in complex regional pain syndrome (CRPS), signal intensity was greater in the CRPS-affected limb than in controls. However, it was not possible to localize heightened expression of α1 -adrenoceptors to nerves, sweat glands, blood vessels, or keratinocytes using this technique. METHODS: To explore this in the present study, skin biopsies were obtained from 31 patients with CRPS type I and 23 healthy controls of similar age and sex distribution. Expression of α1 -adrenoceptors on keratinocytes and on dermal blood vessels, sweat glands, and nerves was assessed using immunohistochemistry. RESULTS: α1 -Adrenoceptors were expressed more strongly in dermal nerve bundles and the epidermis both on the affected and contralateral unaffected side in patients than in controls (P<0.05). However, expression of α1 -adrenoceptors in sweat glands and blood vessels was similar in patients and controls. α1 -Adrenoceptor staining intensity in the CRPS-affected epidermis was associated with pain intensity (P < 0.05), but a similar trend for nerve bundles did not achieve statistical significance. DISCUSSION: Epidermal cells influence nociception by releasing ligands that act on sensory nerve fibers. Moreover, an increased expression of α1 -adrenoceptors on nociceptive afferents has been shown to aggravate neuropathic pain. Thus, the heightened expression of α1 -adrenoceptors in dermal nerves and epidermal cells might augment pain and neuroinflammatory disturbances after tissue injury in patients with CRPS type I.