Recommendations on practice of conditioned pain modulation (CPM) testing.

Protocols for testing conditioned pain modulation (CPM) vary between different labs/clinics. In order to promote research and clinical application of this tool, we summarize the recommendations of interested researchers consensus meeting regarding the practice of CPM and report of its results.

Negative expectations facilitate mechanical hyperalgesia after high-frequency electrical stimulation of human skin.

BACKGROUND: High-frequency electrical stimulation (HFS) of human skin induces not only an increased pain sensitivity in the conditioning area but also an increased pain sensitivity to mechanical punctate stimuli in the non-conditioned surrounding skin area. The aim of the present study was to investigate whether this heterotopically increased mechanical pain sensitivity can be facilitated through the induction of negative expectations. METHODS: In two independent conditions [a nocebo (n = 15) and control condition (n = 15)], we applied mechanical pain stimuli before, directly after, 10 min and 20 min after HFS in the skin area surrounding the conditioning area, and measured the reported pain intensity [visual analogue scale (VAS)]. All subjects (of both conditions) received a written instruction about the HFS protocol, but only the instruction in the nocebo condition was extended by the following text (in Dutch): 'After the HFS, your skin will become more sensitive to the pinprick stimulation'. RESULTS: Our results clearly show that induced expectations of increased mechanical pain sensitivity after HFS facilitates the reported pain intensity after HFS more than when no information is given. CONCLUSIONS: This study shows for the first time that brain mechanisms, via the induction of negative expectations, can facilitate heterotopic mechanical hyperalgesia after HFS of human skin.

Altered central pain processing after pancreatic surgery for chronic pancreatitis.

BACKGROUND: Chronic abdominal pain is common in chronic pancreatitis (CP) and may involve altered central pain processing. This study evaluated the relationship between pain processing and pain outcome after pancreatic duct decompression and/or pancreatic resection in patients with CP. METHODS: Patients with CP underwent quantitative sensory testing. Pain processing was measured via electrical pain detection (ePDT) and electrical pain tolerance (ePTT) thresholds in dermatomes C5 and L4. Inhibitory descending pain control mechanisms were assessed using the conditioned pain modulation (CPM) paradigm. Healthy controls and patients with CP were compared, and patients with CP and a poor pain outcome (visual analogue scale (VAS) score greater than 30) were compared with those with a good pain outcome (VAS score 30 or less). RESULTS: Forty-eight patients with CP had lower ePDT, ePTT and CPM responses compared with values in 15 healthy controls (P < 0·030). The sum of ePDT values was lower in patients with a poor pain outcome than in those with a good outcome (median 7·1 versus 11·2 mA; P = 0·008). There was a correlation with the VAS score and the sum of ePDT values (rs = -0·45, P = 0·016) and ePTT values (rs = -0·46, P = 0·011), and CPM response (rs = -0·43, P = 0·006) in patients with CP. CONCLUSION: After pain-relieving pancreatic surgery, patients with CP exhibit altered central pain processing compared with that in healthy controls. Poor pain outcomes are associated with more central sensitization and more pronociceptive descending pain modulation, and this should be considered when managing persistent pain after pain-relieving surgery for CP.

Role of induced negative and positive emotions in sensitivity to itch and pain in women.

BACKGROUND: Itch and pain are common symptoms in skin disease. It has been suggested that negative emotions may play a role in itch and pain. To date, however, the role of emotions has only been studied for pain in experimental studies, not yet for itch. OBJECTIVES: To investigate the effects of negative and positive emotions on the sensitivity to itch and pain. METHODS: Film fragments were used to induce a negative or positive emotional state in healthy women. Itch and pain were induced using the following somatosensory stimuli: electrical stimulation, histamine iontophoresis and the cold pressor test. RESULTS: Results showed that the scores for itch and pain evoked by histamine and the cold pressor test, respectively, were significantly higher in the negative than in the positive emotion condition, whereas tolerance thresholds to electrical stimulation and the cold pressor test, and stimulus unpleasantness scores did not differ between the two conditions. CONCLUSIONS: These findings for the first time indicate in an experimental design that emotions play a role in sensitivity to somatosensory sensations of both itch and pain.

Bilateral thoracoscopic splanchnicectomy for pain in patients with chronic pancreatitis impairs adrenomedullary but not noradrenergic sympathetic function.

BACKGROUND: Bilateral thoracoscopic splanchnicectomy (BTS) is a well-known technique to alleviate intractable pain in patients with chronic pancreatitis. BTS not only disrupts afferent fibers from the pancreas that mediate pain but also postganglionic sympathetic fibers, which originate in segments T5-T12 and which innervate the vasculature of the liver, pancreas, and the adrenal gland. The purpose of this study was to assess whether and how BTS affects sympathetic noradrenergic and adrenomedullary function in patients with chronic pancreatitis. METHODS: Sixteen patients with chronic pancreatitis for at least 1 year underwent autonomic function testing before and 6 weeks after BTS for intractable pain. Testing was performed during supine rest and during sympathetic stimulation when standing. RESULTS: Supine and standing systolic and diastolic blood pressure were significantly lower post-BTS compared with pre-BTS (P = 0.001). One patient showed orthostatic hypotension after BTS. Baseline plasma norepinephrine levels and plasma norepinephrine responses to sympathetic activation during standing were not reduced by BTS. In contrast, supine plasma epinephrine levels and responses during standing were significantly reduced (P < 0.001). Parasympathetic activity was unaffected by BTS as shown by unaltered Valsalva ratio, I-E difference, and ΔHRmax. CONCLUSIONS: BTS for pain relief in patients with chronic pancreatitis reduced adrenomedullary function, due to disruption of the efferent sympathetic fibers to the adrenal gland. BTS did not affect noradrenergic sympathetic activity, although blood pressure was lower after the sympathectomy.

Increased sympathetic activity in chronic pancreatitis patients is associated with hyperalgesia.

Pain treatment in chronic pancreatitis patients is difficult, with pain frequently relapsing or persisting. Recent studies suggest that altered central nervous system pain processing underlies the chronic pain state in these patients. There is evidence that increased sympathetic activity may also play a role in some chronic pain syndromes. This study assessed sympathetic nervous system activity and its relation to pain processing in patients with severe painful chronic pancreatitis. The authors postulated that chronic pancreatitis patients with more sympathetic activity exhibit more generalized hyperalgesia. In 16 chronic pancreatitis patients, sympathetic activity was measured via venous plasma norepinephrine (NE) levels (supine, standing). Pain processing was quantified via pressure pain tolerance thresholds (PPTs) in dermatomes T10 (pancreatic area), C5, T4, L1. Five patients showed increased supine plasma NE levels (NE ≥ 3.0 nmol/L). PPTs were lower in patients with increased NE levels (INE) compared with patients with normal NE (NNE) (means [95% confidence interval]: INE 402 kPa [286-517] versus NNE 522 kPa [444-600]; P = .042). In severe chronic pancreatitis patients, increased sympathetic activity and hyperalgesia appear associated, suggesting that sympathetic activity may also play a role in these patients' pain.

Generalized and symptom-specific sensitization of chronic itch and pain.

BACKGROUND: Physicians are frequently confronted with patients reporting severe itch and pain. Particularly in patients suffering from persistent itch and pain, central and peripheral sensitization processes are assumed to be involved in the long-term maintenance and aggravation of the symptoms. The present study explores generalized and symptom-specific sensitization processes in patients suffering from persistent itch and pain. Specifically, it examines whether patients with chronic itch and pain are more sensitive to somatosensory stimuli (generalized sensitization) and simultaneously perceive somatosensory stimuli as a symptom of their main physical complaint, e.g. pain in chronic pain patients (symptom-specific sensitization). METHODS: Thresholds for different mechanical and electrical sensory stimuli of Quantitative Sensory Testing were determined in 15 female patients suffering from chronic itch associated with atopic dermatitis, 15 female chronic pain patients diagnosed with fibromyalgia, and 19 female healthy controls. Intensities of itch and pain sensations were rated on a visual analogue scale. RESULTS: As expected, the patient groups had significantly lower tolerance thresholds for the somatosensory stimuli applied than the healthy controls, supporting generalized sensitization. Moreover, patients with chronic itch consistently reported more itch, while patients with chronic pain partly reported more pain in response to analogous somatosensory stimuli than the healthy controls and the other patient group, indicating symptom-specific sensitization. CONCLUSION: The present study provides preliminary support that both generalized and symptom-specific sensitization processes play a role in the regulation and processing of somatosensory stimulation of patients with chronic itch and pain.

Effect of thoracoscopic splanchnic denervation on pain processing in chronic pancreatitis patients.

BACKGROUND: Central sensitisation due to visceral pancreatic nociceptive input may play an important role in chronic pancreatitis pain. Using quantitative sensory testing (QST), this first study investigates whether thoracoscopic splanchnic denervation (TSD), performed to reduce nociceptive visceral input, affects central sensitisation in chronic pancreatitis patients. PATIENTS AND METHODS: We studied 19 chronic pancreatitis patients (11 men, 8 women on stable opioid medication) and 18 healthy volunteers as preoperative controls. Preoperatively and 6 weeks after TSD, pain numeric rating scores, opioid medication, and thresholds to electric skin stimulation and pressure pain (measured in dermatomes T10 (pancreas), C5, T4, L1, L4) were documented. Treatment success was defined as cessation of opioids 6 weeks after TSD. RESULTS: Six weeks after TSD, there was a trend towards lower pain scores, only 10 patients were still on opioids (P<0.05 vs. preoperatively) and thresholds overall were significantly higher than preoperatively (pressure pain: +25%, P<0.001; electric: sensation +55%, pain detection +34%, pain tolerance +21%, P<0.05). Gender-specific differences in hypoalgesia patterns were seen. Preoperatively, TSD treatment successes consumed significantly less opioids than failures, without significant differences in preoperative patterns of neuroplasticity. CONCLUSIONS: TSD for chronic pancreatitis pain resulted in fewer patients on opioids and overall increases in pain thresholds. Our results suggest that TSD for reducing visceral nociceptive input may be effective in reducing resulting central sensitisation. Although patients benefiting from TSD consume less opioids preoperatively, we were unable to clearly link treatment success with specific perioperative patterns of neuroplasticity such as the presence or absence of hyperalgesia.

Chronic post-thoracotomy pain: a retrospective study.

BACKGROUND: Chronic pain is common after thoracotomy. The primary goal of this study was to investigate the incidence of chronic post-thoracotomy pain. The secondary goal was to identify possible risk factors associated with the development of chronic post-operative pain. METHODS: We contacted 255 patients who had undergone a classic postero-lateral thoracotomy at our institution in the period between January 2001 and December 2003. All patients received a letter requesting participation; a questionnaire was included with the letter. One week later patients were contacted by telephone to obtain the answers to the questionnaire. RESULTS: We ultimately obtained results from 149 patients (58% of all thoracotomies, 84% of survivors). The overall incidence of chronic post-operative pain was 52% (32% mild, 16% moderate and 3% severe chronic post-operative pain). Patients with chronic post-operative pain reported acute post-operative pain more frequently than those without (85% vs. 62%, P = 0.01), had more severe acute post-operative pain (P = 0.0001), underwent more extensive surgical procedures (P = 0.01), had more constant acute pain (vs. fluctuating pain or pain in attacks) (P = 0.0004) and reported less absence of pain during the first post-operative week (P = 0.0001). There was no significant decrease in chronic pain with time after thoracotomy. CONCLUSION: Our study confirms that chronic post-thoracotomy pain is a common problem. The results from our study suggest that chronic post-thoracotomy pain may be associated with more intensive and extensive nociceptive input due to thoracic surgery.

Pharmacological management of pain in chronic pancreatitis.

Pain is the major presenting symptom of chronic pancreatitis. Patients with chronic pancreatitis experience substantial impairments in health-related quality of life. Pain may be considered as the most important factor affecting the quality of life. The pathogenesis of pancreatic pain is poorly understood. The cause of pain in chronic pancreatitis is probably multifactorial. This article discusses the various hypotheses that have been suggested to underlie pain. Special attention is paid to the concept of autonomous central sensitisation and hyperalgesia as a cause of pain. Strict abstinence from alcohol is the first step of chronic pancreatic pain management. As a second step, it is important to exclude treatable complications of chronic pancreatitis, such as pseudocysts. Symptomatic treatment with analgesics is often unavoidable in patients with chronic pancreatitis. Acetaminophen, non-steroidal anti-inflammatory drugs and eventually opioids are suitable. Several trials have been performed with pancreatic enzymes, but a meta-analysis demonstrated no significant benefit in terms of pain relief. The treatment of chronic pancreatic pain requires a multidisciplinary approach that tailors the various therapeutic options to meet the need of the individual patient.

Do diagnostic segmental nerve root blocks in chronic low back pain patients with radiation to the leg lack distinct sensory effects? A preliminary study.

BACKGROUND: The present preliminary study documents the effects of a selective nerve root block (SNB) with short or long acting local anaesthetic compared with baseline measurements in patients with chronic low back pain radiating to the leg with maximum pain in one dermatome (L4). METHODS: Ten consecutive patients underwent 20 controlled SNBs at L4 with ropivacaine 0.25% and lidocaine 1% in a prospective, randomized, double blind, crossover fashion. Baseline measurements included sensory function (assessed by pinprick on both unaffected and painful leg) and pain (Verbal Numeric Rating Scale; VNRS, 0-10). A change in size of areas with altered sensory function >10% and a VNRS change of 2 points were considered clinically significant. P-values<0.05 were considered statistically significant. RESULTS: Asymptomatic hypoaesthesia, variable in extent and non-dermatomal in distribution, was present in seven patients at baseline. It appeared to be more extensive and distal with longer duration of pre-existing pain. SNB produced no consistent changes in extent and distribution of hypoaesthetic areas. Change in VNRS did not correlate with the extent of pre-block or post-block hypoaesthesia. No differences in effects were found between lidocaine and ropivacaine. CONCLUSIONS: Pre-block assessment of sensory function is essential to assess the net effect of SNBs. In this small study group, SNBs failed to demonstrate uniform or distinct effects on sensory function.

The management of chronic pain in Switzerland: a comparative survey of Swiss medical specialists treating chronic pain.

Chronic pain management by Swiss specialist physicians with the primary hypothesis that pain clinic practitioners conform better to good practice (interdisciplinarity, diagnostic/therapeutic routines, quality control, education) than other specialists treating chronic pain was surveyed. Management of all types of chronic pain by pain clinic practitioners and rheumatologists, oncologists or neurologists was compared via a mailed questionnaire survey (n=125/group). Two hundred and twenty-nine (46%) of 500 mailed questionnaires were returned with similar group return rates. Eighty-six percent of responders find chronic pain therapy very difficult/difficult; they estimate only 45% of these patients achieve good outcomes. Twenty-three per cent of responders belong to an interdisciplinary pain centre, but 72% of chronic pain patients are treated by responders alone. Fifty-nine percent never/only occasionally use therapeutic algorithms, 38% use formal pain diagnostic procedures, 20% have a pain quality control programme. Fifty-one percent lack past pain education, 37% do not attend continuing pain education, 69% agree that pain education is their greatest need. Pain clinic practitioners are more interdisciplinary and use more pain diagnostics than other specialists. They are matched by oncologists in education and success in therapeutic escalation, and bettered by them in algorithm use. Pain clinic practitioners and oncologists bring particular-differing-skills to chronic pain management compared to rheumatologists and neurologists. Chronic pain management diversity may result from differences in malignant and benign pain, and its generally being provided by the speciality treating the underlying cause. This survey identifies targets for improvement in areas fundamental to good chronic pain practice: interdisciplinarity, diagnostic/therapeutic tools, quality management and education.

Midazolam premedication reduces propofol dose requirements for multiple anesthetic endpoints.

PURPOSE: This study investigates the interactions between midazolam premedication and propofol infusion induction of anesthesia for multiple anesthetic endpoints including: loss of verbal contact (LVC; hypnotic), dropping an infusion flex (DF; motor), loss of reaction to painful stimulation (LRP; antinociceptive) and attainment of electroencephalographic burst suppression (BUR; EEG). METHODS: In a double blind, controlled, randomized and prospective study, 24 ASA I-II patients received either midazolam 0.05 mg x kg(-1) (PM; n = 13) or saline placebo (PO; n = 11) i.v. as premedication. Twenty minutes later, anesthesia was induced by propofol infusion at 30 mg x kg(-1) x hr(-1). ED50, ED95 and group medians for times and doses were determined and compared at multiple anesthetic endpoints. RESULTS: At the hypnotic, motor and EEG endpoints, midazolam premedication significantly and similarly reduced propofol ED50 (reduction: 18%, 13% and 20% respectively; P <0.05 vs unpremedicated patients) and ED95 (reduction: 20%, 11% and 20% respectively; P <0.05 vs unpremedicated patients). For antinociception (LRP), dose reduction by premedication was greater for propofol ED95 (reduction: 41%; P <0.05 vs unpremedicated patients) than ED50 (reduction: 18%; P <0.05 vs unpremedicated patients). Hemodynamic values were similar in both groups at the various endpoints. CONCLUSIONS: Midazolam premedication 20 min prior to induction of anesthesia reduces the propofol doses necessary to attain the multiple anesthetic endpoints studied without affecting hemodynamics in this otherwise healthy population. The interaction differs for different anesthetic endpoints (e.g., antinociception vs hypnosis) and propofol doses (e.g., ED50 vs ED95).

Changes in sensory processing after surgical nociception.

Nociception results in peripheral and central changes in sensory processing. These changes are considered to significantly contribute to postoperative pain and its outcome. Objective measures of changes in sensory processing are now being studied in humans after surgery. Surgical nociception leads to both central excitation (eg, spinal sensitization) and central inhibition (eg, descending inhibition), with inhibition being the dominant response during the first day or so after surgery. Analgesia commenced before surgery (preemptive analgesia) depresses central sensitization and enhances central inhibition. Patients operated on under nonanalgesic anesthesia may exhibit rebound central sensitization for up to 5 days postoperatively after the cessation of postoperative opioid analgesia. There is only a weak relationship between the described objective changes in sensory processing after surgical nociception and subjective clinical pain measures such as pain intensity scales or postoperative analgesic consumption.

Analgesic action of i.v. morphine-6-glucuronide in healthy volunteers.

The pharmacodynamics of morphine-6-glucuronide (M-6-G) i.v. were assessed in 12 healthy male volunteers in an open study. After a single bolus dose of M-6-G 5 mg i.v., we measured antinociceptive effects, using electrical and cold pain tests, and plasma concentrations of M-6-G, morphine-3-glucuronide (M-3-G) and morphine. Pain intensities during electrical stimulation (at 30, 60 and 90 min after injection) and ice water immersion (at 60 min) decreased significantly (P < 0.005) compared with baseline. Mean plasma peak concentrations of M-6-G were 139.3 (SD 38.9) ng ml-1, measured at 15 min. Our data demonstrate that M-6-G has significant analgesic activity.

Slow EEG-power spectra correlate with haemodynamic changes during laryngoscopy and intubation following induction with fentanyl or sufentanil.

We studied nociception-associated arousal following laryngoscopy and intubation in patients scheduled for elective open heart surgery, using EEG power spectra and hemodynamics. Either fentanyl (7 micrograms/kg; n = 30) or sufentanil (1 microgram/kg; n = 30) were given in a randomized fashion to induce anesthesia in heavily premedicated patients, followed by pancuronium bromide (100 micrograms/kg). EEG-power spectra (delta, theta, alpha, beta) as well as mean arterial blood pressure (MAP) and heart rate (HF) were measured at the following end-points: before the induction of anesthesia (control), 1 and 10 minutes after laryngoscopy and intubation (L & I). Linear regression analysis was computed to determine which of the EEG power spectra was most sensitive to detect insufficient blockade of nociceptive-related arousal when correlated with haemodynamics. In the fentanyl group the change in HF closely correlated with the decrease of power in the slow delta- and theta-domain (r2 = 0.98 and r2 = 0.89 respectively) of the EEG. The change in MAP also closely correlated with a decrease in the slow delta- and theta-domain (r2 = 0.97 and r2 = 0.99 respectively). There was little correlation in regard to spectral edge frequency (SEF) and HF and MAP changes (r2 = 0.36 and r2 = 0.12 respectively). In the sufentanil group the change in HF correlated closely with an increase of power in the fast alpha and a decrease in the slow theta-domain (r2 = 0.91 and r2 = 0.98 respectively) of the EEG. The changes in MAP closely correlated with an increase in the fast alpha-band a decrease in the slow theta-domain (r2 = 0.98 and r2 = 0.73 respectively). Also there was little correlation of SEF with HF and MAP changes (r2 = 0.09 and r2 = 0.02 respectively). Among the EEG-spectra, reduction of power in the slow delta- and theta-bands are the most sensitive parameters to determine insufficient antinociception of opioids commonly used for the induction in cardiac anesthesia. Increase of power in the alpha-band seems to be closely correlated with cortical reactivation and reduction of hypnosis, while a reduction of power especially in the deltabut more so in the theta-band of the EEG reflects nociception related arousal.

Midazolam premedication and thiopental induction of anaesthesia: interactions at multiple end-points.

We have studied the effects of midazolam premedication on multiple anaesthetic end-points (hypnotic, loss of verbal contact (LVC); motor, dropping an infusion flex or bag (DF); analgesic, loss of reaction to painful stimulation (LRP); and EEG, attainment of burst suppression (BUR)) during induction by slow thiopental infusion at a rate of 55 mg kg-1 h-1. Patients received midazolam 0.05 mg kg-1 i.v. (group TM, n = 12) or no midazolam (group T0, n = 13). ED50 and ED95 values and group medians for times and doses at the end-points were measured. Midazolam premedication reduced significantly thiopental ED50 and ED95 values at all end-points (exception for ED95 for BUR). Potentiation was greatest for the motor end-point (dropping the infusion bag (DF)) (ED95 +52%, ED50 +23%, median +39%), and smallest for painful stimulation (LRP) (median +18%; ED50 +13%). For LRP and DF, premedication was associated with significant, non-parallel increases in the slope of the thiopental dose-response curves, resulting in marked potency ratio changes from ED50 to ED95 (LRP +31%, DF +29%). There were no such increases for LVC or BUR. The interaction between midazolam and thiopental varied with the anaesthetic end-point and may also depend on the dose of thiopental. Our data suggest that the mechanism of interaction between midazolam premedication and thiopental was different for motor effects or analgesia (DF, LRP) compared with hypnotic effects or cortical depression (LVC, BUR), in agreement with the different central nervous system substrates underlying these distinct anaesthetic end-points.

No inhibition of gastro-intestinal propulsion after propofol- or propofol/ketamine-N2O/O2 anaesthesia. A comparison of gastro-caecal transit after isoflurane anaesthesia.

BACKGROUND: Gastrointestinal motility may be considerably reduced by anaesthesia and or surgery resulting in postoperative ileus. Inhibition of propulsive gut motility is especially marked after an opioid-based technique. Little, however, is known of the gastrointestinal effects of the hypnotic propofol when given continuously over a longer period of time, which is the case in total intravenous anaesthesia (TIVA) and in intensive care sedation. We therefore set out to study the effects of a propofol-based nitrous oxide/oxygen anaesthesia (group PO) on gastro-caecal transit time. The results were compared with a propofol-ketamine technique (group PK) and an isoflurane-based anaesthesia (group I; each group n = 20). METHODS: Gastro-caecal transit was determined by measurement of endexpiratory hydrogen concentration (ppm). Following gastral installation of lactulose at the end of the operation, the disaccharide was degraded by bacteria in the caecum, resulting in the liberation of hydrogen which was expired. A 100% increase in endexpiratory hydrogen concentration compared to the preinduction period was considered the end-point of gastro-caecal transit. RESULTS: There was no significant difference with regard to gastro-caecal transit in the three groups of patients. In the propofol group mean gastro-caecal transit was 119 (+/- 50.6 SD) min, in the propofol-ketamine group it was 147 (+/- 57.4 SD) min, and in the isoflurane group transit time was 122 (+/- 48.6 SD) min. CONCLUSION: The data suggest that propofol, even when given as a continuous infusion, does not alter gastrointestinal tract motility more than a standard isoflurane anaesthesia. The data may be particularly relevant to patients who are likely to develop postoperative ileus. They also suggest that in an ICU setting propofol does not alter gut motility more than a sedation technique with the analgesic ketamine.