An incoherent HIFU transducer for treatment of the medial branch nerve: Numerical study and in vivo validation.

BACKGROUND: Chronic back pain due to facet related degenerative changes affects 4-6 million patients a year in the United States. Patients refractory to conservative therapy may warrant targeted injections of steroids into the joint or percutaneous medial branch nerve denervation with radiofrequency ablation. We numerically tested a novel noninvasive high intensity focused ultrasound transducer to optimize nerve ablation near a bone-soft tissue interface. METHODS: A transducer with 4 elements operating in an incoherent mode was modeled numerically and tested pre-clinically under fluoroscopic guidance. After 6 lumbar medial branch nerve ablations were performed in 2 pigs, they were followed clinically for 1 week and then sacrificed for pathological evaluation. RESULTS: Simulations show that the acoustic spot size in water at 6 dB was 14mm axial x 1.6mm lateral and 52mm axial x 1.6mm lateral for coherent and incoherent modes, respectively. We measured the size of N = 6 lesions induced in vivo in a pig model and compared them to the size of the simulated thermal dose. The best match between the simulated and measured lesion size was found with a maximum absorption coefficient in the cortical bone adjusted to 30 dB/cm/MHz. This absorption was used to simulate clinical scenarios in humans to generate lesions with no potential side effects at 1000 and 1500 J. CONCLUSION: The elongated spot obtained with the incoherent mode facilitates the targeting during fluoroscopic-guided medial branch nerve ablation.

Canadian recommendations for the management of breakthrough cancer pain.

Breakthrough cancer pain (btcp) represents an important element in the spectrum of cancer pain management. Because most btcp episodes peak in intensity within a few minutes, speed of medication onset is crucial for proper control. In Canada, several current provincial guidelines for the management of cancer pain include a brief discussion about the treatment of btcp; however, there are no uniform national recommendations for the management of btcp. That lack, accompanied by unequal access to pain medication across the country, contributes to both regional and provincial variability in the management of btcp. Currently, immediate-release oral opioids are the treatment of choice for btcp. This approach might not always offer optimal speed for onset of action and duration to match the rapid nature of an episode of btcp. Novel transmucosal fentanyl formulations might be more appropriate for some types of btcp, but limited access to such drugs hinders their use. In addition, the recognition of btcp and its proper assessment, which are crucial steps toward appropriate treatment selection, remain challenging for many health care professionals. To facilitate appropriate management of btcp, a group of prominent Canadian specialists in palliative care, oncology, and anesthesiology convened to develop a set of recommendations and suggestions to assist Canadian health care providers in the treatment of btcp and the alleviation of the suffering and discomfort experienced by adult cancer patients.

Development and Implementation of a Registry of Patients Attending Multidisciplinary Pain Treatment Clinics: The Quebec Pain Registry.

The Quebec Pain Registry (QPR) is a large research database of patients suffering from various chronic pain (CP) syndromes who were referred to one of five tertiary care centres in the province of Quebec (Canada). Patients were monitored using common demographics, identical clinical descriptors, and uniform validated outcomes. This paper describes the development, implementation, and research potential of the QPR. Between 2008 and 2013, 6902 patients were enrolled in the QPR, and data were collected prior to their first visit at the pain clinic and six months later. More than 90% of them (mean age ± SD: 52.76 ± 4.60, females: 59.1%) consented that their QPR data be used for research purposes. The results suggest that, compared to patients with serious chronic medical disorders, CP patients referred to tertiary care clinics are more severely impaired in multiple domains including emotional and physical functioning. The QPR is also a powerful and comprehensive tool for conducting research in a "real-world" context with 27 observational studies and satellite research projects which have been completed or are underway. It contains data on the clinical evolution of thousands of patients and provides the opportunity of answering important research questions on various aspects of CP (or specific pain syndromes) and its management.

Correlation of intact sensibility and neuropathic pain-related behaviors in eight inbred and outbred rat strains and selection lines.

In some rat strains, total hindpaw denervation triggers autotomy, a behavior of self mutilation presumably related to neuropathic pain. Partial sciatic ligation (PSL) in rats produces tactile allodynia and heat hyperalgesia but not autotomy. Our aims in this study were to examine: (1) whether sensibility of intact rats to noxious and non-noxious stimuli is strain-dependent; (2) whether sensibility of intact rats could predict levels of autotomy, or of allodynia and hyperalgesia in the PSL model; and (3) whether autotomy levels are correlated with levels of allodynia or hyperalgesia. Here we report that in two inbred rat strains (Lewis and Fisher 344), two outbred rat strains (Sabra and Sprague-Dawley) and four selection lines of rats (Genetically Epilepsy-Prone Rats, High Autotomy, Low Autotomy and Flinders Sensitive Line), tactile sensitivity and response duration to noxious heat of intact animals were strain-dependent. Levels of autotomy following hindpaw denervation and of allodynia and hyperalgesia in the PSL model were also strain-dependent. Thus, these traits are determined in part by genetic factors. Sensory sensibility of intact rats was not correlated with levels of autotomy following total denervation, or allodynia and hyperalgesia following partial denervation. We suggest that preoperative sensibility of intact rats is not a predictor of levels of neuropathic disorders following nerve injury. Likewise, no correlation was found between autotomy, allodynia and hyperalgesia, suggesting that neuropathic pain behaviors triggered by nerve injury of different etiologies are mediated by differing mechanisms.

Heat hyperalgesia following partial sciatic ligation in rats: interacting nature and nurture.

As in humans, levels of neuropathic pain produced by nerve injury are highly variable among animals. This variability was attributed to genetic and environmental factors. For example, we reported that chronic neuropathic sensory disorders developing following total (autotomy) or partial nerve injury (allodynia and hyperalgesia) depended on the diet rats consumed. Here we investigated the interaction between genetic and dietary factors in the development of heat hyperalgesia in rats following partial sciatic ligation (the PSL model). We show that heat sensitivity of intact rats and levels of heat hyperalgesia of PSL-injured rats were highly variable across eight different rat strains and seven different diets. Thus, genetic and environmental variables interact in determination of levels of chronic neuropathic sensory disorders in rats.

Mechano- and thermo-sensitivity in rats genetically prone to developing neuropathic pain.

By selective breeding, lines of rats were derived which consistently expressed high (HA) or low (LA) levels of autotomy following sciatic nerve injury, autotomy being a behavior pattern presumed to reflect the presence of neuropathic paraesthesias and pain. We report here that intact (unoperated) HA and LA rats differ in their responsiveness to cutaneous mechanical and thermal stimuli. Thus, the autotomy trait, which was identified by its expression under conditions of nerve injury, shares determinants with sensory processing channels in the intact animal.

Dietary supplementation with the inhibitory amino acid taurine suppresses autotomy in HA rats.

Taurine is an inhibitory amino acid in the CNS. When supplied to rats it produces analgesia in some acute pain tests. Here we examined the effect of taurine supplementation on sensitivity to pain in intact rats, and whether perioperative dietary supplementation with taurine in rats would suppress autotomy, a behavior produced by peripheral neurectomy and related to neuropathic pain. Thermal pain sensitivity of intact rats consuming 1% taurine in the drinking solution for 2 weeks was not significantly different from that of control rats. Autotomy levels, determined in rats consuming taurine pre-, post- or perioperatively were significantly lower than in matching control groups. We conclude that taurine plays an important role in the autotomy model, presumably by protecting inhibitory neurons in the CNS against an excitotoxic damage triggered by injury discharge and ectopic input from the severed nerves.

Postoperative morbidity is similar in patients anesthetized with epidural and general anesthesia for radical prostatectomy.

OBJECTIVES: To compare the effect of epidural and general anesthesia on the postoperative course and complication rate in patients undergoing radical prostatectomy. METHODS: Ninety-eight men scheduled for radical retropubic prostatectomy (RRP) were randomly assigned to receive epidural anesthesia only (EA, n = 34), combined epidural and general anesthesia (EG, n = 33) or general anesthesia only (GA, n = 31). In the EA group, epidural anesthesia was induced and maintained with bupivacaine. In the EG group, patients received epidural bupivacaine after the induction of general anesthesia. In the GA group, anesthesia was induced with morphine and maintained with isoflurane. In the postoperative period, epidural patient-controlled analgesia (PCA) was maintained in all patients for 3 to 5 days. Patients were evaluated throughout the hospitalization period and at 3, 6, and 12 weeks following surgery. RESULTS: The three groups did not differ with regard to postoperative pain, bleeding, urine output, fever, length of paralytic ileus, or length of hospitalization. No major cardiovascular, pulmonary, or neurologic complications occurred in any of the patients either perioperatively or in the first 3 months postoperatively. CONCLUSIONS: Intraoperative anesthetic technique was not associated with a different postoperative complication rate in patients undergoing RRP. The very low incidence of complications and the uniform postoperative analgesic regimen may have contributed to the similarity between groups.

Intraoperative blood loss during radical retropubic prostatectomy: epidural versus general anesthesia.

OBJECTIVES: There are conflicting reports on the influence of different anesthetic techniques, such as regional versus general anesthesia, on intraoperative blood loss. The purpose of this study was to elucidate the effects of anesthetic technique on intraoperative blood loss in men undergoing radical retropubic prostatectomy (RRP). METHODS: One hundred patients undergoing RRP for prostate cancer were randomly assigned to receive either epidural anesthesia (EA), combined epidural and general anesthesia (EG), or general anesthesia alone (GA). Intraoperative blood loss was calculated by using a formula that accounted for the volume and hematocrit of the fluid suctioned from the surgical field, blood absorbed on surgical pads, and the patient's hematocrit. RESULTS: Mean blood loss in the EA group (1490 +/- 90 mL; mean +/- SEM) was significantly less than mean blood loss in both the EG group (1810 +/- 100 mL) and the GA group (1940 +/- 130 mL) (P = 0.01). Blood loss was not different between the EG and the GA groups (P = 0.7). Significantly less blood was transfused during surgery in the EA group (730 +/- 50 mL) compared with the EG (960 +/- 60 mL) and GA (950 +/- 70 mL) groups (P = 0.02). CONCLUSIONS: Similar blood loss in patients receiving general anesthesia, either alone or when combined with epidural anesthesia, implies that epidural anesthesia did not reduce bleeding, but, rather, that general anesthesia increased blood loss.

A-fibers mediate mechanical hyperesthesia and allodynia and C-fibers mediate thermal hyperalgesia in a new model of causalgiform pain disorders in rats.

Unilateral tight ligation of about half of the sciatic nerve in rats rapidly produces sympathetically dependent neuropathic pain which lasts many months and resembles causalgia in humans. The sensory abnormalities detected at the plantar side of the hindpaws include: (1) nocifensive responses to repetitive light touch (allodynia); (2) bilateral reduction in withdrawal thresholds to repetitive von-Frey hair stimulation (mechanical hyperesthesia); (3) bilateral reduction in withdrawal thresholds to CO2 laser heat pulses; and (4) unilateral increase in response duration to an intense laser heat pulse (thermal hyperalgesia). Using neonatal capsaicin treatment, we determined the type of afferent fiber remaining in the partially injured nerve, which mediates these disorders. Capsaicin, which destroys most C- and some A delta-fibers in peripheral nerves, had no effect on the touch-evoked allodynia and mechanical hyperesthesia that are produced by partial sciatic nerve injury. These disorders were, therefore, mediated by myelinated fibers. In contrast, thermal hyperalgesia failed to develop in capsaicin-treated rats following partial nerve injury. Thus, thermal hyperalgesia produced by partial nerve injury appears to be mediated by heat-nociceptive C-fibers.

Diet can modify autotomy behavior in rats following peripheral neurectomy.

Partial sciatic nerve ligation in rats (PSL) produces neuropathic pain disorders [Seltzer, Z., Dubner, R. and Shir, Y., Pain, 43 ( 1990) 205-18 (corrected) ]. Recently we reported that diet markedly affected the levels of these disorders. Here we questioned whether diet also affects neuropathic pain-related behavior in another model, produced by total denervation of the hindpaw following peripheral sciatic and saphenous neurectomy. Sabra rats and HA line rats were fed for 2-3 weeks preoperatively and up to 58 days postoperatively (PO) with one of five different diet formulas. We found that the autotomy behavior differed significantly between the diet groups. Surprisingly, in some diets the effects on autotomy and PSL models were different and even contrasting. Modulation of diet in humans may emerge as a novel therapy of neuropathic pain.

Neuropathic pain following partial nerve injury in rats is suppressed by dietary soy.

Some humans with partial nerve injury present a syndrome of neuropathic sensory disorders which depend on the sympathetic activity (sympathetically-maintained pain, SMP). Several years ago we introduced a rat model for SMP, produced by tightly ligating 1/3-1/2 of the sciatic nerve, leading to a partial denervation of the hindpaw (Partial Sciatic Ligation, PSL model) [Seltzer, Z., Dubner, R. and Shir, Y., Pain, 43 (1990) 245-250]. After working with this model for several years we encountered difficulties in replicating it although rat strain, vendor, gender, age and weight, surgical approach and sensory testing procedures were not changed. We report here that this variability can be attributed, at least in part, to the diet the animals consumed. Rats fed perioperatively with soy-containing diets expressed significantly weaker neuropathic sensory disorders compared to rats fed on soy-free diets. We conclude that diet may greatly affect experimental outcome in the PSL model.

Life-threatening torsade de pointes arrhythmia associated with head injury.

Torsade de pointes (atypical ventricular tachycardia) occurred in a 75-year-old man 1 day after blunt head injury, in association with a focal intracerebral hematoma in the left thalamic area. The causal relationship between the traumatic stimulation of the left sympathetic pathway and the development of this life-threatening arrhythmia is discussed.

Continuous epidural methadone treatment for cancer pain.

Seventy cancer patients suffering from visceral or somatic pain received continuous epidural methadone (EM) analgesia. Initially, 4 mg of 0.1% methadone was given three times daily. If this dose proved ineffective, it was gradually increased to 8 mg four times daily. With this regimen good pain control was obtained in 56 patients (80%). Patients continued the EM therapy for periods up to 140 days, with an average duration of 27 days. Morphine was substituted for methadone in 14 patients (20%). Four of these patients responded well and continued treatment for an average of 18 days. No serious side effects have been observed with EM. With a proper selection of patients and following strict therapy guidelines, epidural methadone is efficacious in treating cancer pain.

Oral methadone for the treatment of severe pain in hospitalized children: a report of five cases.

OBJECTIVE: Pain relief is still inadequate in many hospitalized patients, especially children in whom suboptimal use of analgesic drugs is still common. In the past 2 years, oral methadone has been used extensively in our institution for treating children with persistent pain from cancer, burns, or trauma who were capable of oral intake and whose pain was not relieved by nonopioid medications. SETTING: Tertiary university hospital. PATIENTS: Of the 70 children treated thus far with oral methadone, five are described in the present report. MAIN OUTCOME MEASURE: Pain relief, acceptability, and side effects of oral methadone in children with pain. RESULTS: Treatment with oral methadone (0.1% in 10% glucose, dose range of 0.2-0.6 mg/kg/day) for time periods of up to 6 weeks resulted in a rapid onset and stable pain relief, with no major side effects. No adverse responses were encountered after discontinuation of treatment. In three of the children, a parent-controlled analgesia regimen was successfully employed. CONCLUSIONS: Oral methadone can be recommended for babies and children who have severe pain that is not alleviated by nonopioid medications and who are capable of oral intake.

Sympathetically-maintained causalgiform disorders in a model for neuropathic pain: a review.

Partial nerve injury is the main cause of sympathetically maintained causalgiform pain disorders in humans. We present here an animal model of this condition, produced in rats by a unilateral ligation of about half of the sciatic nerve. Starting hours after the operation and for several months thereafter, the rats developed signs of spontaneous pain, touch-evoked allodynia and hyperesthesia, and mechanical and thermal hyperalgesia in the partially denervated as well as the intact contralateral foot. These disorders were maintained by the sympathetic outflow and disappeared following postoperative sympathectomy. In neonatally capsaicinated rats we found that touch-evoked allodynia and hyperesthesia were mediated by A-fibers whereas thermal hyperalgesia was mediated by C-fibers. These disorders were not due to receptor sensitization of remaining afferent fibers by prostaglandins. We found strain differences and genetic inheritance of these causalgiform disorders which were correlated with the expression of autotomy to hind-paw denervation.

A randomized trial of fluoxetine versus amitriptyline in musculo-skeletal pain.

In a preclinical study we found fluoxetine alone to induce a serotonin-mediated, dose-dependent antinociceptive effect in the mouse hot plate assay. In the present study we evaluated the clinical implication of these findings, comparing the efficacy of fluoxetine with that of amitriptyline for musculo-skeletal pain. Forty non-depressed patients, suffering from low back pain and whiplash associated cervical pain were enrolled in a randomized, six-week, "blind-rater" study, comparing the analgesic effect of amitriptyline (50-75 mgs/day) with that of fluoxetine (20 mgs/day). Twenty patients were randomly assigned to the amitriptyline group, and twenty to the fluoxetine group. Visual analogue and verbal rating scales were used for the assessment of pain intensity and pain relief. Thirty-five patients concluded the study. Moderate or good relief of pain was reported by 14 of the 17 patients (82%) in the amitriptyline group, and by 14 of the 18 patients (77%) in the fluoxetine group. The difference in responses between amitriptyline and fluoxetine was not statistically significant. In our study, fluoxetine relieved low back pain and whiplash associated cervical pain with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the tricyclic antidepressants' side effects.

[Neuropathic pain unrelieved by morphine, alleviated by haloperidol].

Neuropathic pain, originating in damaged nerve and not peripheral nociceptors, is often resistant to treatment by opiates given by the oral, parenteral or spinal routes. This failure to obtain satisfactory pain relief is generally ascribed to psychological factors or to individual peculiarities in drug metabolism or kinetics. Currently, psychotropic and antidepressant drugs are among the first choices in treating painful conditions due to partial nerve lesions. We present a 56-year-old man who suffered intractable pain confined to his left knee following emergency L2-3 vertebral decompression, after collapse due to metastatic disease. 12 mg of morphine and 10 of diazepam given together intravenously did not lessen pain. Acute, solitary spinal nerve root injury was hypothesized. 2 mg of haloperidol injected IV gave complete relief of pain without hypotension or deep sedation. There is no definite explanation for the resistance of neuropathic pain to opiates.

[Treating hospitalized children in severe pain with oral methadone].

Pain relief is usually inadequate in hospitalized patients, especially in children, either after surgery or with various medical conditions. Among other reasons, this is due to suboptimal use of available analgesic drugs. In the past 2 years oral methadone has become our opioid of choice for severe pain in hospitalized children who can take oral medication. More than 70 babies and children, aged 8 months to 9 years, who suffered mainly from pain due to burns or cancer, were treated by the in-hospital pain service. They received 0.1% methadone syrup, 0.2-0.4 mg/kg/day, for from a few days to more than a month. In most there was significant pain relief with no serious side-effects. In some, treatment could be changed to parent-controlled analgesia after a few days, with no adverse effects. We describe 5 of the children who present the advantages of oral methadone over other opioids.

[Continuous intercostal nerve block for chronic pain].

21 ambulatory patients with acute or chronic pain localized to the chest, were treated successfully by continuous intercostal block. They included 6 women and 15 men, aged 39-70. Treatment was initiated in the outpatient clinic and continued at home for usually 5-6 days. Between 15-20 ml of 0.5% marcaine were continuously injected over the course of 6-12 hours through a catheter introduced into the intercostal space by a Touhy needle. 76% of the patients had substantial relief of pain during the block and required only minimal systemic medication. During a 3 month follow-up after cessation of the block, up to 65% were still pain-free. Results were poor or only fair in those with malignancy and long-standing intercostal neuralgias. There were no serious side-effects during treatment. This method is an important new tool in the treatment of pain.