CLINICAL PHARMACODYNAMICS
Clin Drug Invest 1999 Jan; 17 (1): 33-42 1173-2563/99/0001-0033/$05.00/0 © Adis International Limited. All rights reserved.
Dynorphin A(1-13) Analgesia in Opioid-Treated Patients with Chronic Pain A Controlled Pilot Study
Russell K. Portenoy,1 Augusto Caraceni,1 Nathan I. Cherny,1 Ronald Goldblum,2 Jane Ingham,1 Charles E. Inturrisi,3 Jian H. Johnson,2 Jeanne Lapin,1 Paul J. Tiseo1 and Mary Jeanne Kreek4 1 2 3 4
Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, NY, USA Neurobiological Technologies Inc., Richmond, CA, USA Department of Pharmacology, Cornell University Medical College, New York, NY, USA Laboratory on Biology of Addictive Disease, Rockefeller University, New York, NY, USA
Abstract
Objective: This pilot study was developed to acquire preliminary data concerning the analgesic efficacy and tolerability of dynorphin A(1-13), a 13 amino acid fragment of the endogenous opioid peptide dynorphin A(1-17), in opioid-treated patients. Design and Setting: Randomised, double-blind, placebo-controlled, graded dose, 3-way crossover pilot study conducted in a comprehensive cancer centre. Patients: Nine chronic pain patients receiving morphine >150 mg/day for at least 2 weeks, or the equivalent dose of hydromorphone. Interventions: Each patient was given a study treatment on each of 3 successive days after the opioid regimen was stabilised. On each day, a patient received 50% of the usual oral opioid dose when pain was at least moderate, followed 15 minutes later by a brief intravenous infusion of either dynorphin A(1-13) 150 μg/kg, dynorphin A(1-13) 500 μg/kg, or saline placebo. The sequence of administration was randomly ordered. Main Outcome Measures: Pain intensity, pain relief, mood and adverse effects were recorded for 8 hours after each treatment. Blood was sampled for dynorphin levels beginning 15 minutes after the infusion. Results: The data demonstrated linear dose-response trends for most of the parameters evaluated. Using analysis of variance (ANOVA), the differences among lower dose dynorphin A(1-13), higher dose dynorphin A(1-13), and the control were strongest for the sum of pain intensity differences (categorical scale) [p = 0.08], peak relief (p = 0.10), and total mood effect (p = 0.08). Post hoc pairwise comparisons consistently demonstrated the largest differences between the higher dose dynorphin A(1-13) and control. The major adverse effect was flushing. Dynorphin was detected only in the first sample, which was drawn 15 minutes after drug administration. Conclusions: This controlled pilot study identified trends suggesting that a brief intravenous infusion of dynorphin A(1-13) could potentially augment analgesia in opioid-treated patients. Based on this experience, a larger controlled trial is warranted. A 500 μg/kg dose would be an appropriate minimum dose for such studies.
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The dynorphins comprise a series of peptides derived from proteolytic processing of the opioid precursor molecule prodynorphin. These molecules are extensively distributed in the CNS and may be involved in diverse opioid-mediated functions, including the response to noxious stimulation and other stressors, and regulation of autonomic, hormonal, and immune systems.[1,2] Dynorphin A(1-17) and its fragment dynorphin A(1-13) were the first of these peptides to be isolated,[3] and have been best characterised pharmacologically. Both binding and pharmacological assays indicate that these compounds interact with μ, δ and κ opioid receptors, but have strongest affinity for the κ subtype.[4-7] Extensive studies of dynorphin pharmacology in animal models suggest that these compounds play a complex role in the processing of nociceptive input and the response to exogenous opioids. Although some studies have suggested that intracerebral administration of dynorphin A(1-17), or a variety of its fragments, produce antinociceptive effects,[7-10] others demonstrated no such effects when the drug was administered alone. [11-13] Coadministration of dynorphin with a μ-agonist opioid yields effects that appear to vary with the prior opioid exposure of the animal. Specifically, dynorphin antagonises analgesia produced by morphine or β-endorphin in opioid-naive animals, but potentiates analgesia in opioid-tolerant animals.[11,14] These results suggest a modulatory role for dynorphin in the analgesia produced by μ-agonists. The potentiation of analgesia in opioid-tolerant animals may be brought about by mechanisms that produce analgesia directly or those that involve a reversal of analgesic tolerance. The importance of the latter process gains support from the observation that dynorphin peptides can affect physical dependence to μ-agonist opioids. For example, dynorphin peptides can prevent abstinence in both morphine-dependent animals[14-17] and humans who are physically dependent on heroin.[18] Recent in vitro studies of a mouse dorsal root ganglion preparation suggest that dynorphin could © Adis International Limited. All rights reserved.
Portenoy et al.
reverse tolerance through blockade of excitatory opioid receptor functions.[19] Other studies suggest that these actions on physical dependence may involve a nonopioid mechanism,[16,17] at least in part. Studies of dynorphin analgesia following administration by other routes have yielded similarly complex results. Although several investigations have suggested that intrathecal administration of dynorphin A(1-13) is antinociceptive in animals,[8,20-22] these findings are difficult to interpret given concurrent motor effects. At high doses, intrathecal dynorphin produces a flaccid paraplegia,[20] and one study could not identify any antinociceptive activity at doses below those associated with adverse motor effects.[23] There is also evidence that the spinal antinociceptive effects of dynorphin A(1-13), if indeed they exist, may not be mediated by a receptor.[22,23] Intravenous dynorphin A(1-13) has also produced antinociceptive effects in the mouse writhing assay.[24] This action, which may involve a peripheral mechanism, appears to be produced through a nonopioid mechanism. Thus, animal studies have neither established nor refuted a primary analgesic action of dynorphin. If such an analgesic action occurs, it may be mediated either in the CNS (probably at the spinal level) or in the periphery, and may involve both opioid and nonopioid mechanisms. Moreover, this action may be complemented by a partial reversal of analgesic tolerance in opioid-treated animals, which may also potentiate analgesia. The relative importance of these varying mechanisms cannot be discerned from the extant data. Limited human studies do not clarify this complex pharmacology but do suggest that the effects produced by dynorphin could have therapeutic relevance. In small controlled trials, intrathecal dynorphin A(1-13) and dynorphin A(1-10) amide were well tolerated and produced analgesic effects.[25-27] This analgesia was not dose dependent. The degree to which it was influenced by prior opioid exposure was not explored. Together, these data suggest that exogenously administered dynorphin peptides could potentially Clin Drug Invest 1999 Jan; 17 (1)
Dynorphin A(1-13) Analgesia
yield clinically meaningful analgesia in either opioid-naive or opioid-treated patients. Patients who are receiving long-term opioid therapy could potentially experience enhanced analgesia as a primary effect of dynorphin or through reversal of tolerance. If this enhanced analgesia occurred without a worsening of adverse effects, dynorphin may be a useful co-analgesic in the clinical setting. To explore this possibility, a pilot study was designed to evaluate the tolerability and analgesic outcomes associated with dynorphin administration in patients who were receiving long-term opioid therapy. The aim was to discern analgesic trends while assessing the doses that may be needed to exert clinically relevant effects, and the adverse effect liability that may be associated with analgesia. Methods This pilot study evaluated the tolerability and efficacy of single graded doses of dynorphin A(1-13) in opioid-treated patients using a randomised, double-blind, placebo-controlled, 3-way crossover design. It was conducted under the Investigational New Drug (IND) registration (IND #34,155) for dynorphin A(1-13) held by Neurobiological Technologies, Inc. (Richmond, California, USA). The Institutional Review Board of Memorial SloanKettering Cancer Center approved the study, and all patients gave written consent prior to participation. Procedures
Adult patients who had chronic pain and were receiving an oral opioid regimen equivalent to 150mg of oral morphine per day for at least 2 weeks were eligible for the trial. Patients were excluded if: laboratory screening identified a serum creatinine greater than 2.0 mg/dl; hepatic transaminases or serum bilirubin were greater than two times the upper limit of the normal range; or cardiac, pulmonary, neurological or psychiatric disease was severe enough to interfere with opioid therapy, increase the risks associated with dynorphin, or impair data collection. © Adis International Limited. All rights reserved.
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Consenting patients who met inclusion and exclusion criteria were first entered into an opioid stabilisation phase, the goal of which was to stabilise the opioid regimen using short-acting morphine or hydromorphone. Depending on the opioid used prior to recruitment, patients were treated with either immediate-release morphine or hydromorphone at a starting dose based on the prior opioid regimen. A supplemental ‘as needed’ dose of the same drug was provided for breakthrough pain; this supplemental dose was equal to 10% of the total daily dose. The patient was contacted on a daily basis by a study nurse, who assessed average pain intensity during the prior day (using a verbal categorical scale), opioid adverse effects, and use of supplemental opioid doses for breakthrough pain. Based on this information, the investigator adjusted the dose of the short-acting morphine or hydromorphone. In the absence of intolerable adverse effects, the scheduled opioid dose, which was taken five or six times per day, was increased by 30 to 50% if pain intensity was greater than moderate or more than four supplemental opioid doses were taken. The dose could be lowered by this amount if uncomfortable adverse effects occurred. The dose of the supplemental opioid was changed with each adjustment of the baseline dose to maintain it at approximately 10% of the total daily dose. Adjustment of the scheduled and supplemental doses continued until the patient reported ‘adequate’ analgesia, which was defined as an overall daily pain intensity of moderate or less, the use of four or fewer supplemental opioid doses per day, and the experience of no intolerable opioid adverse effects. MPAC Recording
Throughout the stabilisation phase, each patient also recorded pain intensity three times per day using the Memorial Pain Assessment Card (MPAC). The MPAC is a validated scale that comprises two measures of pain intensity [an 8-point categorical scale and a 100mm visual analogue scale (VAS)], a 100mm VAS for pain relief, and a 100mm VAS for mood.[28] The categorical scale rates pain intenClin Drug Invest 1999 Jan; 17 (1)
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sity using the following descriptors: ‘no pain’, ‘just noticeable’, ‘weak’, ‘mild’, ‘moderate’, ‘strong’, ‘severe’ and ‘excruciating’. At each assessment time, the patient was instructed to circle one descriptor. The descriptors used to anchor the VAS were ‘least possible pain’ and ‘worst possible pain’ for pain intensity, ‘no relief of pain’ and ‘complete relief of pain’ for pain relief, and ‘worst mood’ and ‘best mood’ for mood. At each assessment time, the patient was instructed to indicate the pain intensity, pain relief, and mood ‘right now’ by marking the respective VAS. The use of the MPAC during the stabilisation period allowed the patient to become familiar with this instrument, which was also used to acquire the primary outcome data on pain and pain relief after administration of each study drug. The patient could enter the study phase after ‘adequate’ analgesia had been recorded for at least 2 days. Each patient visited the clinic on 3 separate days during the study phase. A maximum of 5 days was allowed to accomplish the three visits. The patients were instructed to eat the same breakfast on each of the 3 study days. On each of these days, the patient was told to report to the clinic in the morning without taking the usual first dose of morphine or hydromorphone. After arrival at the clinic, an intravenous catheter was placed in each arm. A study nurse assessed pain using the simple verbal rating scale that was applied during the stabilisation phase. If the patient was not experiencing at least moderate pain, no action was taken and the pain was reassessed approximately 30 minutes later. Such reassessments continued until pain increased. When the patient reported at least moderate pain, 50% of the stabilised morphine or hydromorphone dose was administered by the oral route. Fifteen minutes later, a brief intravenous infusion (15 minutes in duration) was administered. The infusion contained either saline placebo, a lower dose of dynorphin A(1-13) [150 μg/kg], or a higher dose of dynorphin A(1-13) [500 μg/kg]. The sequence of administration varied, and each patient was randomly assigned to a sequence. The six possible se© Adis International Limited. All rights reserved.
Portenoy et al.
quences were randomly ordered and consecutive patients were assigned to a sequence in this order. Dynorphin A(1-13) was supplied by Neurobiological Technologies, Inc. (Richmond, California, USA) as a sterile lyophilised powder in glass vials. Prior to administration, the compound was reconstituted by a study pharmacist using saline. The reconstituted drug was colourless, and identical in appearance to the saline control. Assessments
Patients were assessed with the MPAC prior to administration of the oral opioid and again prior to the study treatment. After the study treatment was administered, assessments were performed every 10 minutes for the first half-hour, every 15 minutes for the next hour, and then every 30 minutes until 8 hours passed or the patient requested remedication with an analgesic. At each of these subsequent assessment points, patients completed an MPAC and responded to a query about adverse effects. Adverse effects that were volunteered were rated on a three-point intensity scale (mild, moderate or severe). Blood was sampled from the intravenous catheter in the arm contralateral to the catheter that received the infusion. Samples were taken prior to the administration of the study drug (placebo or dynorphin) and at 15, 30, 45, 60, 90, 120 and 180 minutes after the infusion. At the end of the study period, a blood sample was also taken to evaluate blood count and serum chemistries. Blood assays for total dynorphin immunoreactivity were performed by Dr G. Hochhaus using a direct immunoassay with a detection limit of 150 ng/L. The assay method is described elsewhere.[28] Stabilised, extracted blood samples were stored frozen until assayed. As noted, data were collected for 8 hours or until analgesic remedication was requested by the patient following each dose of study drug. After the first and second doses, patients restarted their baseline opioid regimen (scheduled dose and supplemental doses as needed). Although most clinic visits occurred on consecutive days, an interposed weekend or holiday would increase the Clin Drug Invest 1999 Jan; 17 (1)
Dynorphin A(1-13) Analgesia
interval between some doses to as many as 3 days. In all cases, the three doses were administered within a 5-day period. On each day between doses, the MPAC was again completed three times and the number of supplemental opioid doses was recorded. After the third dose of study drug, patients returned to their baseline opioid regimen. Data Analysis
Analgesic responses to each of the three study infusions were primarily determined from analysis of the MPAC data. On the 8-point categorical scale, each descriptor was assigned a numerical score (no pain = 1, just noticeable = 2, weak = 3, mild = 4, moderate = 5, strong = 6, severe = 7, and excruciating = 8). The numerical scores for each VAS was determined as the number of millimetres from the left end of the 100mm scale to the patient’s mark. Pain intensity differences (PID) were calculated from both the MPAC categorical scale and the VAS for pain intensity. The PIDs were calculated by subtracting the measurement obtained immediately before the study treatment (dynorphin or saline) from each of the pain measurements obtained thereafter. In two patients, the MPAC measurements prior to the study treatment were mistakenly deleted; the pre-opioid dose MPAC scores were carried forward in these cases to provide the baseline for calculation of the PIDs. The sums of these pain intensity differences (SPID) over time were calculated to approximate an area under the curve (AUC) for the change in pain intensity. SPIDs were determined for both the categorical scale (SPID-CAT) and the VAS (SPID-VAS). After remedication, the pain intensity differences were considered to be ‘0’ for the calculation of these SPIDs. The pain relief VAS yielded a score for each assessment time. To approximate an AUC for pain relief over time, each of these scores was summed to yield a total pain relief (TOTPAR). After remedication, relief was considered to be ‘0’ for the calculation of TOTPAR. The largest relief score was also analysed as a measure of peak relief. © Adis International Limited. All rights reserved.
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Other measures of analgesia included peak PID scores, the time until remedication was requested by the patient after each dose of study drug, and the time until pain intensity had declined by 50% after the dose. To approximate peak change in pain, the largest PID was calculated for both the categorical scale (PID-CAT) and the VAS (PID-VAS). The ‘pain half gone’ measure also was derived from the categorical scale and VAS for pain intensity. Nonanalgesic effects monitored during the study comprised mood scores on the MPAC and adverse effects. Differences among treatments in mood effects were determined using the sum of the mood scores obtained during each assessment time (TOTMOOD). Overall comparisons across the three treatments were performed using analysis of variance (ANOVA) for a crossover design. Where appropriate, post hoc pairwise tests were used to explore differences between treatments. The median time to remedication and the time to ‘pain half gone’ were evaluated with the Wilcoxon test. Adverse effects and their associated severity ratings were tabulated by treatment. A priori, an α level of p = 0.10 was considered a statistical trend warranting further post hoc analyses. This decision reflected the pilot nature of the study, which sought to capture trends that could be useful in the design of future studies. In nine patients, a significance level of p = 0.10 would detect a difference equal to 1.2 times the standard deviation with a power of 0.80. Results Nine patients, seven women and two men, were recruited for the study. All met eligibility criteria, provided informed consent, and completed the study. Demographic and disease-related characteristics varied (table I). All patients had been treated with opioid drugs for a prolonged period. During the stabilisation period, the average number of opioid doses taken per day was 4.5 (range 3.6 to 5.7) and the average number of supplemental doses per day was 1.7 (range 0 to 3.2). The mean total daily opioid dose at the end of the stabilisation Clin Drug Invest 1999 Jan; 17 (1)
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Portenoy et al.
period was equivalent to 296mg of oral morphine (range 150 to 990mg). Treatment Efficacy
The ANOVA for the SPID-CAT over the 8-hour study period and the ANOVA for peak relief approached significance (p = 0.08 and p = 0.10, respectively) and favoured the active treatments over the control (table II). The ANOVA for the SPID-VAS (p = 0.43) and for peak change in pain intensity (p = 0.62 for the VAS and p = 0.42 for the categorical scale) were not significant. TOTPAR over the 8-hour study period also was not significant (p = 0.19), but the active treatments were favoured over the control (table II). Finally, the ANOVA for TOTMOOD over the 8-hour period also approached significance (p = 0.08) and again favoured the study treatments (table II).
Selected post hoc pairwise comparisons were used to further explore treatment differences when the ANOVA suggested a trend. The assessment of SPID-CAT yielded significant differences between higher dose dynorphin and control (p = 0.03), and a trend towards significance of the difference between lower dose dynorphin and control (p = 0.10) [table III]. For both peak relief and TOTMOOD, there were significant differences between higher dose dynorphin and control (p = 0.04 and p = 0.04, respectively) and trends towards significance between higher dose dynorphin and lower dose dynorphin (p = 0.10 and p = 0.07, respectively). To further assess dose-response trends, other post hoc analyses were performed. The differences in median time to remedication were not significantly different, but favoured the higher dose dynorphin (90 minutes for the saline control, 75 minutes for lower dose dynorphin, and 150 minutes
Table I. Characteristics of study patients Pt no.
Age (y)
Gender
Race
Height (cm)
Weight (kg)
Diagnosisa
1
44
F
Caucasian
170
61.8
Spinal stenosis
150
2
56
M
Caucasian
183
76.6
Chest wall pain (mesothelioma)
195
3
48
F
Black
158
50.9
Abdominal pain (Gardner’s syndrome) 195
4
30
F
Caucasian
152
67.9
Reflex sympathetic dystrophy
5
60
F
Black
170
69.0
Reflex sympathetic dystrophy
180
6
51
M
Caucasian
175
72.5
Throat pain (head/neck cancer)
990
7
41
F
Caucasian
157
58.2
Failed low back pain syndrome
176
8
47
F
Caucasian
175
80.5
Face pain (postsurgical)
255
9
33
F
Caucasian
152
50.9
Idiopathic
270
Mean (SD)
45.6 (20.0)
165.8 (27.9)
65.4 (24.1)
a
Pain diagnosis.
b
Total daily opioid dose taken on the last day of the stabilisation period.
Opioid doseb (mg)
255
296 (263.4)
Table II. Efficacy variables. p-Value is for overall ANOVA. For area-under-the-curve parameters (SPID, TOTPAR and TOTMOOD), the models evaluated the full 8-hour assessment period. See text for abbreviations Control [mean (SD)]
Dynorphin 150 μg/kg [mean (SD)]
Dynorphin 500 μg/kg [mean (SD)]
p-Value
SPID-CAT
0.17 (0.96)
–0.42 (0.84)
–0.61 (0.81)
0.08
SPID-VAS
2.67 (14.49)
–4.67 (14.04)
–4.47 (13.05)
0.43
TOTPAR
12.74 (11.97)
18.06 (19.23)
25.25 (22.65)
0.19
Peak PID-CAT
–1.89 (1.17)
–2.44 (2.4)
–2.67 (1.74)
0.42 0.62
Peak PID-VAS
–34.56 (23.35)
–42.44 (36.6)
–42.00 (24.24)
Peak relief
58.56 (28.92)
63.00 (37.77)
77.78 (25.59)
0.10
TOTMOOD
19.89 (15.81)
21.47 (16.71)
33.71 (23.55)
0.08
© Adis International Limited. All rights reserved.
Clin Drug Invest 1999 Jan; 17 (1)
Dynorphin A(1-13) Analgesia
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Table III. Pairwise comparisons of efficacy data. For area-under-the-curve parameters (SPID, TOTPAR and TOTMOOD), the models evaluated the full 8-hour assessment period. See text for abbreviations Higher dose vs control (p-value)
Lower dose vs control (p-value)
Higher vs lower dose (p-value) 0.57
SPID-CAT
0.034
0.10
Peak relief
0.04
0.62
0.10
TOTMOOD
0.04
0.80
0.07
for higher dose dynorphin). An analysis that compared each patient’s time to remedication following administration of the saline control with the time to remedication following the higher dynorphin dose also favoured dynorphin (p = 0.08). The analysis of the ‘pain half gone’ measurement did not yield any meaningful trends. Dynorphin Plasma Concentrations
The quantity of dynorphin and the metabolites measured by the assay was usually highest at the time of the first blood sample, which was drawn 15 minutes following the infusion, and rapidly declined thereafter to levels below precise quantitation. Accordingly, there were no meaningful plasma profiles determined for either the lower dose dynorphin or the higher dose dynorphin. Adverse Events
There were no serious adverse events during the study and no patient was withdrawn from the study as a result of an adverse event. There were no clinically important changes in vital signs at any point during the three study phases and there were no changes in laboratory screening parameters as a result of the study treatments. However, at least one adverse event was reported by five of the nine patients after receiving placebo, eight of the nine patients after receiving lower dose dynorphin, and all patients after receiving higher dose dynorphin. In total, 55 adverse events were reported by the nine patients. Eight events followed placebo administration, 17 followed dynorphin 150 μg/kg, and 30 followed dynorphin 500 μg/kg. © Adis International Limited. All rights reserved.
The two most common adverse effects were the sensation of flushing and somnolence. Flushing occurred once after placebo and lower dose dynorphin administration, and 10 times after higher dose dynorphin administration. Somnolence did not appear to be dose dependent; it occurred five times after lower dose dynorphin, three times after placebo, and twice after higher dose dynorphin. Other common adverse effects, which occurred only after the administration of dynorphin 500 μg/kg and related temporally with the flushing, were a tingling sensation (seven patients), dizziness (five patients), and itching (five patients). No classical dysphoria or psychotomimetic symptoms were reported. Of the 55 adverse events, 21 were described as severe. All severe events occurred following the administration of higher dose dynorphin. Seven of the 21 severe events comprised flushing, and the remainder were variable and included dizziness, itch, anxiety, tingling, nausea, dry mouth, generalised burning sensation, sleepiness, localised irritation at the infusion site, and sweating. All severe adverse events were transitory, with resolution usually occurring within 1 hour of the dose. All patients recovered fully. Discussion Studies of dynorphin A(1-17), dynorphin A(1-13), and other fragments of the prodynorphin precursor molecule indicate that these endogenous opioid peptides play a complex role in antinociceptive processing. In animal models, dynorphin compounds can be shown to have both primary analgesic effects, which may be mediated either in the CNS[8,20-22] or the periphery,[24] and modulatory Clin Drug Invest 1999 Jan; 17 (1)
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effects, which may influence the analgesic responses to μ-agonist opioids.[11,14] These modulatory effects may involve processes that reverse analgesic tolerance and physical dependence.[14-17] The antinociceptive effects produced by dynorphin appear to be mediated by both opioid and nonopioid mechanisms,[17,24] and the opioid effects may be mediated by both κ and non-κ receptors.[22,23] Together, these data indicate that dynorphin is a unique opioid compound, which could potentially produce actions relevant to the treatment of clinical pain. Early human studies confirmed that dynorphin compounds can yield analgesia in patients with some prior or concurrent opioid exposure,[25-27] but provided little insight into the tolerability, efficacy or clinical utility of any particular peptide. These controlled trials used intrathecal administration, a route that would not be acceptable given the risk of adverse motor effects now identified in animals.[20] Parenteral administration in humans was investigated in a recent dose escalation study of dynorphin A(1-13), which established that single intravenous doses between 30 and 2000 μg/kg were well tolerated in methadone-treated patients with chronic pain,[29] and a study of the hormonal effects of Dyn A(1-13).[2] There are sufficient data to warrant the clinical investigation of dynorphin compounds as potential analgesics for human use, but the diversity of findings in preclinical studies and the limited clinical data to date do not allow informed judgements concerning the type of patient population best suited for trials or the likelihood that systemic administration will yield clinically meaningful outcomes. Pilot trials may be useful in this situation to clarify the likelihood of a favourable therapeutic index for the treatment of pain, and the dose range that produces meaningful effects. When subjective effects are the primary outcomes of interest, as they are in analgesic studies, the credibility of a pilot trial depends on the methodological controls that can be incorporated into the evaluation. The present study incorporated the use of random assignment, double-blind drug © Adis International Limited. All rights reserved.
Portenoy et al.
administration, graded doses and placebo control, validated assessment measures, and concurrent monitoring of drug concentration to enhance the value of the results. The objective was to provide an initial evaluation of dynorphin A(1-13) in patients with substantial prior opioid exposure. It was surmised that such patients, who may be subject to both primary analgesic effects and reversal of analgesic tolerance, would be most likely to show effects from the administration of this compound. The clinical population that provided the study sample, those with refractory chronic pain, have an ongoing need for new drugs that may enhance opioid analgesia or improve the balance between analgesia and adverse effects. Should this pilot trial demonstrate tolerability and provide some evidence of efficacy in the dose range evaluated, the design of a more definitive study in this population would be greatly facilitated. Efficacy was evaluated with the MPAC, a validated measure that includes redundant scales for pain intensity (categorical and visual analogue), a scale for pain relief, and a mood scale.[30] Summary measures, which evaluated both area under the time-action curves and peak effects, demonstrated mixed results, with several findings that suggested a dose response and favoured higher dose dynorphin over the lower dose dynorphin or saline control. Such trends in a pilot study of only nine patients suggest that intravenous dynorphin A(1-13) might have meaningful effects on analgesia and mood in patients with substantial opioid exposure. They warrant further study in a larger controlled analgesic trial. Based on the present results, a dose of 500 μg/kg should be considered the minimum for future single-dose studies. The decision to pursue additional evaluations of dynorphin as a therapeutic agent would depend on further clarification of the dose response and therapeutic index in patients with varying degrees of prior opioid exposure. If meaningful analgesia could only be achieved with a relatively high dose, or if analgesia was commonly compromised by adverse effects, the drug would not have utility as Clin Drug Invest 1999 Jan; 17 (1)
Dynorphin A(1-13) Analgesia
an adjuvant agent for patients requiring longterm opioid therapy. The results of this pilot trial do not illuminate these issues and suggest only that there may be a rationale for additional investigation in a better defined dose range. The inability to measure meaningful plasma profiles of dynorphin or its metabolites precluded an informative pharmacokinetic-pharmacodynamic analysis of the efficacy data. The pharmacokinetics of dynorphin are complex and the assay methodology is evolving.[31,32] The pharmacokinetics of dynorphin were not well characterised when this study was designed. The lack of measurable total dynorphin by 15 minutes is consistent with what is known about the kinetics of this compound, primarily as studied ex vivo, and suggests that prolonged analgesia, if it occurs, is related either to a metabolite that is not measured by this assay or to a unique mechanism. Future studies may be able to quantitate the biotransformation products of dynorphin A(1-13), which have been defined qualitatively [primary dynorphin A(1-12), A(2-12), and A(4-12)], and may further illuminate the relationships between pharmacokinetics and effects.[31,32] Although most patients had adverse effects, dynorphin A(1-13) was generally well tolerated in this study. There were no serious adverse events, and the most common adverse effect was flushing, which usually followed the higher dose. Although always transitory, the flushing was sometimes severe and could be distressing. This adverse effect has been observed previously[29] and, based on anecdotal observation, is believed to be related to the rate of intravenous administration. A slower rate of infusion in future studies might reduce the incidence of this effect and allow the evaluation of higher doses. The common report of dose-dependent adverse effects raises the possibility of incomplete blinding during this study. This potential confounding factor was not specifically assessed and highlights the tentative nature of the efficacy data. Other limitations included the small sample size and the possibility of carryover effects, which could potentially © Adis International Limited. All rights reserved.
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influence either the efficacy or the adverse effect data. The design of future studies should address these potential limitations. This pilot trial was not designed to characterise the degree to which enhanced analgesia following administration of dynorphin to opioid-treated patients was due to direct analgesic effects, reversal of tolerance, or both. Additional studies are needed to determine which of these varying mechanisms may be operating and clarify the effect of prior and concurrent opioid administration on dynorphin effects. If the analgesic efficacy of dynorphin A(1-13) is confirmed, these studies will also need to determine maximal effects, the outcomes associated with repeated doses or continuous infusion, and the influence of various patient co-morbidities on the incidence and severity of adverse events. Acknowledgements This study was supported by a grant from Neurobiological Technologies, Inc., Richmond, California, and by grants DA 01457 (CEI), DA 05130 (MJK, CEI), and DA 00049 (MJK).
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Correspondence and reprints: Dr Russell K. Portenoy, Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, First Avenue at 16th Street, New York, NY 10003, USA. E-mail:
[email protected]
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