One-Year Results of Prospective Research Study Using 10 kHz Spinal Cord Stimulation in Persistent Nonoperated Low Back Pain of Neuropathic Origin: Maiden Back Study.

PURPOSE: Spinal cord stimulation (SCS) is a recommended treatment for chronic neuropathic pain. Persistent nonoperative low back pain of neuropathic origin has profound negative impacts on patient's lives. This prospective, open label, research study aimed to explore the use of SCS in patients with associated features of central sensitisation such as allodynia and hyperalgesia. MATERIALS AND METHODS: Twenty-one patients with back pain and hyperalgesia or allodynia who had not had prior spinal surgery underwent a SCS trial followed by full implantation. SCS comprised administering electrical impulses epidurally at a frequency of 10 kHz and pulse width of 30 µsec. Patients attended follow-up visits after 6 and 12 months of SCS. Repeated measure ANOVAs/Friedman tests explored change after 6 and 12 months of 10 kHz SCS. Independent sample t-tests/Mann-Whitney U tests examined differences in response after 12 months of 10 kHz SCS. RESULTS: Back and leg pain, quality of life (QoL), pain-related disability, and morphine equivalence significantly improved compared with baseline following 6 and 12 months of 10 kHz SCS. There were no increases in the consumption of opioids, amitriptyline, gabapentin or pregabalin in any patient. After 12 months of treatment, 52% encountered ≥50% improvement in back pain, 44% achieved remission (0-3 cm back pain VAS), 40% reported ODI scores between 0 and 40 and 60% experienced a reduction of at least 10 ODI points. Patients reporting ≥10-point improvement in ODI had significantly longer pain history durations and experienced significantly greater improvements in back pain, leg pain and QoL than those reporting <10-point improvement in ODI. CONCLUSION: The 10 kHz SCS improved back and leg pain, QoL, pain-related disability and medication consumption in patients with nonoperative back pain of neuropathic origin. With further research incorporating a sham control arm, the efficacy of 10 kHz SCS in this patient cohort will become more established.

A Single Site Population Study to Investigate CYP2D6 Phenotype of Patients with Persistent Non-Malignant Pain.

Background and Objectives: Codeine requires biotransformation by the CYP2D6 enzyme, encoded by the polymorphic CYP2D6 gene, to morphine for therapeutic efficacy. CYP2D6 phenotypes of poor, intermediate, and ultra-rapid metabolisers are at risk of codeine non-response and adverse drug reactions due to altered CYP2D6 function. The aim of this study was to determine whether genotype, inferred phenotype, and urinary and oral fluid codeine O-demethylation metabolites could predict codeine non-response following a short course of codeine. Materials and Methods: There were 131 Caucasians with persistent pain enrolled. Baseline assessments were recorded, prohibited medications ceased, and DNA sampling completed before commencing codeine 30 mg QDS for 5 days. Day 4 urine samples were collected 1-2 h post morning dose for codeine O-demethylation metabolites analysis. Final pain assessments were conducted on day 5. Results: None of the poor, intermediate, ultra-rapid metabolisers and only 24.5% of normal metabolisers responded to codeine. A simple scoring system to predict analgesic response from day 4 urinary metabolites was devised with overall prediction success of 79% (sensitivity 0.8, specificity 0.78) for morphine and 79% (sensitivity 0.76, specificity 0.83) for morphine:creatinine ratio. Conclusions: In conclusion, this study provides tentative evidence that day 4 urinary codeine O-demethylation metabolites could predict non-response following a short course of codeine and could be utilised in the clinical assessment of codeine response at the point of care to improve analgesic efficacy and safety in codeine therapy. We offer a scoring system to predict codeine response from urinary morphine and urinary morphine:creatinine ratio collected on the morning of day 4 of codeine 30 mg QDS, but this requires validation before it could be considered for use to assess codeine response in clinical practice.

24-Month Outcomes of Indirect Decompression Using a Minimally Invasive Interspinous Fixation Device versus Standard Open Direct Decompression for Lumbar Spinal Stenosis: A Prospective Comparison.

Purpose: An early-stage, multi-centre, prospective, randomised control trial with five-year follow-up was approved by Health Research Authority to compare the efficacy of a minimally invasive, laterally implanted interspinous fixation device (IFD) to open direct surgical decompression in treating lumbar spinal stenosis (LSS). Two-year results are presented. Patients and Methods: Forty-eight participants were randomly assigned to IFD or decompression. Primary study endpoints included changes from baseline at 8-weeks, 6, 12 and 24-months follow-ups for leg pain (visual analogue scale, VAS), back pain (VAS), disability (Oswestry Disability Index, ODI), LSS physical function (Zurich Claudication Questionnaire), distance walked in five minutes and number of repetitions of sitting-to-standing in one minute. Secondary study endpoints included patient and clinician global impression of change, adverse events, reoperations, operating parameters, and fusion rate. Results: Both treatment groups demonstrated statistically significant improvements in mean leg pain, back pain, ODI disability, LSS physical function, walking distance and sitting-to-standing repetitions compared to baseline over 24 months. Mean reduction of ODI from baseline levels was between 35% and 56% for IFD (p<0.002), and 49% to 55% for decompression (p<0.001) for all follow-up time points. Mean reduction of IFD group leg pain was between 57% and 78% for all time points (p<0.001), with 72% to 94% of participants having at least 30% reduction of leg pain from 8-weeks through 24-months. Walking distance for the IFD group increased from 66% to 94% and sitting-to-standing repetitions increased from 44% to 64% for all follow-up time points. Blood loss was 88% less in the IFD group (p=0.024) and operating time parameters strongly favoured IFD compared to decompression (p<0.001). An 89% fusion rate was assessed in a subset of IFD participants. There were no intraoperative device issues or re-operations in the IFD group, and only one healed and non-symptomatic spinous process fracture observed within 24 months. Conclusion: Despite a low number of participants in the IFD group, the study demonstrated successful two-year safety and clinical outcomes for the IFD with significant operation-related advantages compared to surgical decompression.

Bolus intrathecal injection of ziconotide (Prialt®) to evaluate the option of continuous administration via an implanted intrathecal drug delivery (ITDD) system: a pilot study.

OBJECTIVES: This study evaluated efficacy and safety of bolus doses of ziconotide (Prialt®, Eisai Limited, Hertfordshire, UK) to assess the option of continuous administration of this drug via an implanted intrathecal drug delivery system. MATERIALS AND METHODS: Twenty adults with severe chronic pain who were under consideration for intrathecal (IT) therapy were enrolled in this open label, nonrandomized, pilot study. Informed consent was obtained. Demographics, medical/pain history, pain scores, and concomitant medications were recorded. A physical examination was performed. Creatine kinase was measured. Initial visual analog scale (VAS), blood pressure, heart rate, and respiratory rate were recorded. All patients received an initial bolus dose of 2.5 mcg ziconotide; the dose in the subsequent visits was modified according to response. Subsequent doses were 2.5 mcg, 1.2 mcg, or 3.75 mcg as per protocol. A good response (≥30% reduction in baseline pain VAS) with no side-effects on two occasions was considered a successful trial. Data were analyzed using a generalized estimating equations model, with pain VAS as the outcome and time (seven time points; preinjection and one to six hours postinjection) as the predictor. RESULTS: Generalized estimating equations analysis of summary measures showed a mean reduction of pain VAS of approximately 25% at the group level; of 11 responders, seven underwent pump implantation procedure, two withdrew because of adverse effects, one refused an implant, and one could not have an implant (lack of funding from the Primary Care Trust). CONCLUSIONS: Our data demonstrated that mean VAS was reduced by approximately 25% at the group level after IT ziconotide bolus. Treatment efficacy did not vary with sex, center, age, or pain etiology. Ziconotide bolus was generally well tolerated. Larger studies are needed to determine if bolus dosing with ziconotide is a good predictor of response to continuous IT ziconotide via an intrathecal drug delivery system.

Transcutaneous electrical nerve stimulation for phantom pain and stump pain in adult amputees.

Following amputation, 50% to 90% of individuals experience phantom and/or stump pain. Transcutaneous electrical nerve stimulation (TENS) may prove to be a useful adjunct analgesic intervention, although a recent systematic review was unable to judge effectiveness owing to lack of quality evidence. The aim of this pilot study was to gather data on the effect of TENS on phantom pain and stump pain at rest and on movement. Ten individuals with a transtibial amputation and persistent moderate-to-severe phantom and/or stump pain were recruited. Inclusion criteria was a baseline pain score of ≥3 using 0 to 10 numerical rating scale (NRS). TENS was applied for 60 minutes to generate a strong but comfortable TENS sensation at the site of stump pain or projected into the site of phantom pain. Outcomes at rest and on movement before and during TENS at 30 minutes and 60 minutes were changes in the intensities of pain, nonpainful phantom sensation, and prosthesis embodiment. Mean (SD) pain intensity scores were reduced by 1.8 (1.6) at rest (P < 0.05) and 3.9 (1.9) on movement (P < 0.05) after 60 minutes of TENS. For five participants, it was possible to project TENS sensation into the phantom limb by placing the electrodes over transected afferent nerves. Nonpainful phantom sensations and prosthesis embodiment remained unchanged. This study has demonstrated that TENS has potential for reducing phantom pain and stump pain at rest and on movement. Projecting TENS sensation into the phantom limb might facilitate perceptual embodiment of prosthetic limbs. The findings support the delivery of a feasibility trial.

Perceptual embodiment of prosthetic limbs by transcutaneous electrical nerve stimulation.

OBJECTIVES: In able-bodied participants, it is possible to induce a sense of perceptual embodiment in an artificial hand using a visual-tactile illusion. In amputee patients, electrical stimulation of sensory afferents using transcutaneous electrical nerve stimulation (TENS) has been shown to generate somatic sensations in an amputee's phantom limb(s). However, the effects of TENS on the perceptual embodiment of an artificial limb are not known. Our objective was to investigate the effects of TENS on the perceptual embodiment of an artificial limb in fully intact able-bodied participants. MATERIALS AND METHODS: We used a modified version of the rubber hand illusion presented to 30 able-bodied participants (16 women, 14 men) to convey TENS paresthesia to an artificial hand. TENS electrodes were located over superficial radial nerve on the lateral aspect of the right forearm (1 cm proximal to the wrist), which was hidden from view. TENS intensity was increased to a strong non-painful TENS sensation (electrical paresthesia) was felt beneath the electrodes and projecting into the fingers of the hand. The electrical characteristics of TENS were asymmetric biphasic electrical pulsed waves, continuous pulse pattern, 120 Hz pulse frequency (rate), and 80 µs pulse duration (width). RESULTS: Participants reported significantly higher intensities of the rubber hand illusion during the two TENS conditions (mean = 5.8, standard deviation = 1.9) compared with the two non-TENS conditions (mean = 4.9, standard deviation = 1.7), p < 0.0005. CONCLUSIONS: Our findings provide initial evidence that TENS paresthesia can be projected into an artificial limb, and this can enhance the sense of perceptual embodiment of an artificial hand. Further exploratory studies involving an amputee population are warranted.

The Identification of Blood Biomarkers of Chronic Neuropathic Pain by Comparative Transcriptomics.

In this study, we recruited 50 chronic pain (neuropathic and nociceptive) and 43 pain-free controls to identify specific blood biomarkers of chronic neuropathic pain (CNP). Affymetrix microarray was carried out on a subset of samples selected 10 CNP and 10 pain-free control participants. The most significant genes were cross-validated using the entire dataset by quantitative real-time PCR (qRT-PCR). In comparative analysis of controls and CNP patients, WLS (P = 4.80 × 10-7), CHPT1 (P = 7.74 × 10-7) and CASP5 (P = 2.30 × 10-5) were highly significant, whilst FGFBP2 (P = 0.00162), STAT1 (P = 0.00223), FCRL6 (P = 0.00335), MYC (P = 0.00335), XCL2 (P = 0.0144) and GZMA (P = 0.0168) were significant in all CNP patients. A three-arm comparative analysis was also carried out with control as the reference group and CNP samples differentiated into two groups of high and low S-LANSS score using a cut-off of 12. STAT1, XCL2 and GZMA were not significant but KIR3DL2 (P = 0.00838), SH2D1B (P = 0.00295) and CXCR31 (P = 0.0136) were significant in CNP high S-LANSS group (S-LANSS score > 12), along with WLS (P = 8.40 × 10-5), CHPT1 (P = 7.89 × 10-4), CASP5 (P = 0.00393), FGFBP2 (P = 8.70 × 10-4) and FCRL6 (P = 0.00199), suggesting involvement of immune pathways in CNP mechanisms. None of the genes was significant in CNP samples with low (< 12) S-LANSS score. The area under the receiver operating characteristic (AUROC) analysis showed that combination of MYC, STAT1, TLR4, CASP5 and WLS gene expression could be potentially used as a biomarker signature of CNP (AUROC - 0.852, (0.773, 0.931 95% CI)).

A service improvement project to review prescribing information provided by general practitioners for new referrals to a UK National Health Service hospital pain clinic: potential implications of CYP2D6 enzyme inhibition.

INTRODUCTION: Chronic pain is often managed using co-prescription of analgesics and adjuvants, with concomitant medication prescribed for comorbidities. Patients may have suboptimal response to some analgesics or be at risk of drug interactions or adverse drug reactions (ADRs) due to polypharmacy affecting CYP2D6 enzyme activity. The aim of the service improvement project was to determine the proportion of patients referred to a specialist pain service in the UK National Health Service (NHS) by general practitioners (GPs) who may be at risk of suboptimal analgesic response or ADRs due to CYP2D6 inhibition through polypharmacy. This was achieved by reviewing clinical prescribing information provided by GPs at time of referral. It was hoped that the findings could be used to aid clinical and prescribing decisions without conducting CYP2D6 genotyping or phenotyping. METHODS: A review of letters from 250 patients referred to an NHS hospital pain service from GPs over a 3-month period was undertaken. Information about current and concomitant medications was analysed to identify the potential for CYP2D6 inhibition and adverse events. RESULTS: Letters failed to provide information about current pain medication for 20 (8%) patients or non-pain concomitant medication for 54 (21.6%) patients. Of 176 patients, 52 (29.5%) patients with information about non-pain concomitant medication had been prescribed at least one known CYP2D6 inhibitor. A total of 35 (19.9%) patients were identified as being at risk of an adverse drug reaction and 33 (18.75%) patients at risk of suboptimal analgesic response due to co-administration of CYP2D6 inhibitors. CONCLUSION: The review revealed the need for improved detail in GP referral letters used to transfer care to UK NHS hospital pain clinics. There is a need to consider an individual's CYP2D6 phenotype when prescribing analgesic prodrugs to manage persistent pain. Caution is needed when patients are co-prescribed codeine or tramadol with selective serotonin reuptake inhibitors (SSRIs).

Feasibility study of Transcutaneous Electrical Nerve Stimulation (TENS) for cancer bone pain.

UNLABELLED: This multicenter study assessed the feasibility of conducting a phase III trial of transcutaneous electrical nerve stimulation (TENS) in patients with cancer bone pain recruited from palliative care services. Eligible patients received active and placebo TENS for 1 hour at site of pain in a randomized crossover design; median interval between applications 3 days. Responses assessed at 30 and 60 minutes included numerical and verbal ratings of pain at rest and on movement, and pain relief. Recruitment, tolerability, adverse events, and effectiveness of blinding were also evaluated. Twenty-four patients were randomised and 19 completed both applications. The intervention was well tolerated. Five patients withdrew: 3 due to deteriorating performance status, and 2 due to increased pain (1 each following active and placebo TENS). Confidence interval estimation around the differences in outcomes between active and placebo TENS suggests that TENS has the potential to decrease pain on movement more than pain on rest. Nine patients did not consider that a placebo was used; the remaining 10 correctly identified placebo TENS. Feasibility studies are important in palliative care prior to undertaking clinical trials. Our findings suggest that further work is required on recruitment strategies and refining the control arm before evaluating TENS in cancer bone pain. PERSPECTIVE: Cancer bone pain is common and severe, and partly mediated by hyperexcitability. Animal studies suggest that Transcutaneous Electrical Nerve Stimulation can reduce hyperalgesia. This study examined the feasibility of evaluating TENS in patients with cancer bone pain in order to optimize methods before a phase III trial.

Transcutaneous electrical nerve stimulation (TENS) for cancer bone pain.

In the cancer population, painful bony metastases are common, difficult to treat and significantly reduce quality of life. Common treatments include opioid analgesics, bisphosphonates, and radiotherapy; yet these have significant side effects and are not universally effective. Transcutaneous electrical nerve stimulation (TENS) is inexpensive, relatively free from side effects, and widely available. We present a case study of successful TENS therapy in a patient with cancer bone pain and discuss the rationale for using TENS in this setting.