C.J. Glynn

Morphine responsiveness of chronic pain: double-blind randomised crossover study with patient-controlled analgesia.

There is controversy about whether the lack of response of some chronic pain to opioid treatment is absolute or relative. It is widely believed that nociceptive pain is responsive to opioids whereas neuropathic pain tends not to be. We have used a method of patient-controlled analgesia (PCA) with simultaneous nurse-observer measurement of analgesia, mood, and adverse effects to address these issues. Ten patients with chronic pain were given morphine at two concentrations (10 and 30 mg/ml) by PCA in two separate sessions in a double-blind randomised crossover study. Before the study a clinical judgment was made as to whether each pain was nociceptive or neuropathic. Seven patients showed good analgesic responses (more than 70 mm pain relief on a visual-analogue scale) of pain at rest, two patients poor responses (less than 30 mm pain relief), and one a moderate response with both concentrations (30-70 mm pain relief). The response to morphine was consistent (greater and faster relief with the higher concentration) in nine patients. Two patients had pain on movement that responded moderately to low-concentration morphine and well to the higher concentration. All patients with pains judged to be nociceptive showed good analgesic responses compared with half of those with neuropathic pain. There was no evidence that analgesic responses in patients with neuropathic pain were due to changes in mood. This PCA method is a quick and efficient tool to determine the consistency of the analgesic response. Such consistency can guide the clinician as to whether continued or higher-dose opioid treatment will produce good analgesia. An inconsistent response points to the use of other pain-relieving strategies.

Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design

&NA; The aim was to compare the analgesic effectiveness and adverse effect incidence of oral dextromethorphan (DM) with placebo in patients with neuropathic pain. The first 10‐day treatment period was a multiple‐dose double‐blind randomised controlled cross‐over comparison of 13.5 mg of DM 3 times a day (t.d.s.) with placebo t.d.s.: 5 treatment pairs, each pair 1 day DM and 1 day placebo. The second 10‐day treatment period used 27 mg of DM t.d.s. vs. placebo, with the same design. The study incorporated a 5 pair n‐of‐1 design for each of the 2 doses of DM. Patients took the study medication in addition to any pre‐existing analgesic regime. Patients who reported benefit could continue with DM after the study. Nineteen patients with chronic neuropathic pain were studied over two 10‐day treatment periods. Outcome measures were pain intensity, pain relief, adverse effects, mood, sleep and global rating of treatment. These were recorded by daily patient diaries and by clinic assessments before and after each treatment period. There were no significant differences between DM and placebo on any of the clinic assessment outcome measures. Two patients had significantly better analgesia on more than one outcome measure on within‐patient testing. One had better analgesia with DM. The other had better analgesia with placebo. Ten patients had no adverse effects on either dose of DM. Two patients withdrew during the first treatment period because of adverse effects (which included increased pain intensity), and 5 during the second period. Five patients continued with DM after the study for 1–3 months. No long‐term clinical benefit was apparent in those who continued with open DM. Dextromethorphan at either 40.5 or 81 mg daily did not relieve neuropathic pain.

Intravenous regional sympathetic blockade for pain relief in reflex sympathetic dystrophy: A systematic review and a randomized, double-blind crossover study

The first aim was a systematic review of intravenous regional sympathetic blocks (IRSBs) in patients with reflex sympathetic dystrophy (RSD). Randomized controlled trials (RCTs) of IRSBs in patients with RSD were identified by MEDLINE search (1966 to May 1993) and by hand search of 30 journals (1950 to May 1993). Authors of eligible trials were asked for information on additional trials and for unpublished data. Seven RCTs of IRSBs in RSD were found. Four used guanethidine; none showed significant analgesic effect in IRSBs to relieve pain due to RSD. Two reports, one using ketanserin and one bretylium, with 17 patients in total, showed some advantage of IRSBs over control. RCT results were not combined because of the variety of different drugs and outcome measures and because of methodological deficiencies in most of the reports. The second aim was a randomized, double-blind, crossover study to assess the effectiveness of IRSBs with guanethidine. Patients fulfilling diagnostic criteria for RSD and who had reported pain relief after an open IRSB with guanethidine received IRSBs with guanethidine high dose, guanethidine low dose, and normal saline. Pain intensity and relief, adverse effects, mood, duration of analgesia, and global scores were recorded. Sixteen patients with diagnosis of RSD were recruited, but only nine entered the double-blind phase. The trial was stopped prematurely because of the severity of the adverse effects. No significant difference was found between guanethidine and placebo on any of the outcome measures.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of spinal noradrenergic system in transmission of pain in patients with spinal cord injury

15 patients with deafferentation pain due to spinal cord injury were investigated for a spinal mechanism of pain transmission. Epidural morphine 5 mg in 5 ml of water had an analgesic effect in 5 patients, 3 of whom also had pain relief with epidural clonidine. Epidural clonidine 150 micrograms in 5 ml of saline had an analgesic effect in 7 patients who did not respond to epidural morphine. Neither epidural morphine nor clonidine was effective in the other 3 patients, 2 of whom obtained relief with epidural buprenorphine 0.3 mg in 5 ml of saline. 1 patient did not find relief with any of the injections. These data suggest that a spinal noradrenergic system may be as important as the opioid system in the transmission of pain in patients with spinal cord injury.

Opioid sensitivity of chronic pain: a patient-controlled analgesia method

Twenty‐two patients with chronic pain of malignant or nonmalignant origin were given intravenous morphine by patient‐controlled analgesia. A prestudy judgment was made from the characteristics of the pain as to whether it was nociceptive or neuropathic. Analgesic efficacy was assessed by a nurse‐observer; adverse events were noted and plasma morphine and metabolitie concentrations measured. Three categories of opioid response were distinguished. Good responders obtained > 70 mm relief on the visual analogue scale, with minimal or manageable adverse events. Moderate responders obtained < 70 but > 30 mm relief with more problematic adverse events, and poor responders had < 30 mm relief with troublesome adverse events. This method for the study of opioid sensitivity allowed a wide dosage range to be studied. The simultaneous analgesic and adverse event measurements showed that the spectrum of observed response was wide, and response category could be judged for the majority by 4 h. In those with poor or moderate response, adverse event severity limited further dose increment. The relationship between pain characteristics and response showed that some pains judged to be neuropathic had a good response to opioid (5/13), and some pains judged to be nociceptive did not (5/14). The study suggests that the pattern of response is not as black and white as the prediction of good response from nociceptive pain and poor from neuropathic pain would suggest, although nociceptive pain was more likely than neuropathic pain to show a good response. For the moderate responders opioid titration may, in the absence of other effective treatments, be useful, but the analgesic endpoint may not be totally satisfactory. The method provides an operational definition of opioid sensitivity.

Cerebrospinal fluid kinetics of epidural clonidine

threshold or mechanically unresponsive afferents. These stimuli damage the skin and could alter receptor properties. To avoid this pitfall, we have developed an electrocutaneous search strategy that allows the identification of an RF for these mechanically insensitive afferents @IAs) without applying the adequate stimulus. METHODS: Using teased-fiber techniques in pentobarbital-anesthetized monkeys, we conducted a survey of the response properties of either all A5 or all C fibers identified from distal electrical stimulation of the nerve. Electrocutaneous stimulation was used to identify an “electrical RF” of the mechanically insensitive fibers. RESULTS : Of the 120 A6 fibers identified from distal nerve stimulation, 72 were studied in detail. Electrical RFs were located for 34 fibers that did not respond to gentle pinching or innocuous thermal stimuli. Many of these A5 MIAs responded to intense mechanical stimuli (threshold > 7 bars) applied to a single, punctate location within the electrical RF. Of the 29 MIAs tested with heat, a total of 12 were activated. Of these 12, 2 did not respond to forceps pinch, and 7 others responded to a rapid-onset heat stimulus (49W with a short-latency, quickly-adapting discharge. Chemical sensitivity was tested in 6 MIAs using intradermal injection of 10 ug capsaicin; 3 of the 5 that responded were mechanically unresponsive. Of the 92 C-fibers identified from distal nerve stimulation, 49 were studied in detail. Fifteen did not respond to gentle pinching or innocuous thermal stimuli. For 10 of the 15 fibers, a mechanical RF (threshold L 11 bars) was found within the electrical RF. The remaining 5 fibers did not respond to intense mechanical, thermal, or chemical stimuli and may have been CONCLUSIONS: A large proportion of A5 and C-fibers are stimuli, yet may have an important function in nociception fibers may play a role in pain evoked by chemical and heat

The use of unconventional analgesics in the treatment of chronic pain — A placebo controlled n of 1 multiple dose comparison of dothiepin, amitriptyline & clonazepam

AIM The aim of this study was to compare the analgesic efficacy of selected antidepressant/anti-convulsant drugs in patients with chronic pain conditions, using an “n of 1” design. Using dothiepin vs placebo (n=38), amitriptyline 25 mg vs placebo (n=20) and clonaxepam 0.5, 1 .O 8~ 1.5 mg vs placebo (n=201. m Out-patients were studied for up to 6 weeks in this randomised, double-blind multiple-dose crossover study (3 weeks active or placebo followed by 3 weeks placebo or active treatment). Clinic assessments were made at 0, 3 and 6 weeks; pain was assessed using categorical verbal rating charts, visual analogue scales and the McGill Pain Questionnaire. Assessments for pain intensity, pain relief, side effects and global score were made (daily) by the patients in diaries using the Oxford Pain Chart. At the end of the study period patients were asked to make a preference for either treatment 1 or 2. m Results for the completed studies will be presented. The evolving method has shown sensitivity, and to date with dothiepin the three week treatment period has proved to be adequate for assessment. There are significant differences between the two treatments for the Global Score weeks 2 & 3; AUC diary Pain Intensity score week 2 & 3; and afher treatment for McGill Total score, Typical Pain Intensity, Vas Pain Relief, and the overall patient Global Score.