The aim of this study was to better understand the relationship between morphine and butorphanol analgesic efficacy tested against multiple pain modalities within the same individuals
Participants included healthy men (n=72) and women (n=67) who underwent thermal, pressure, and ischemic experimental pain testing prior to and following the double-blind administration of morphine and butorphanol during separate testing sessions
Factor analysis revealed six factors with analgesic effects grouped primarily by pain modality and specific to either morphine or butorphanol.
Hierarchical cluster analysis of individual factor scores led to four distinct drug response profiles.Three groups displayed exceptional analgesic efficacy produced by one type of opioid on one pain stimulus modality, while the fourth drug response profile was characterized by average analgesic efficacy across all pain modalities for both opioids
These findings suggest that opioids with varying efficacy at the mu and kappa receptors produce independent effects on unique pain mechanisms and that individual responsiveness for some is dependent on pain mechanism and opioid type, although a subset of the population is moderately responsive to opioids regardless of efficacy of receptor binding or predominant pain mechanism being activated.
Although opioids are the most widely used medication for the management of moderate to severe pain, ability to predict which opioid is best suited to treat a particular individual or pain condition remains limited
Considerable preclinical and clinical evidence demonstrates that opioid efficacy varies across experimental pain modality
While the dependence of analgesic efficacy on pain modality has been clearly demonstrated in preclinical research, less is known about how different analgesics compare to one another in response to different experimental pain stimuli among humans. Neural circuits associated with distinct physiological responses are differentially populated by opioid receptor subtypes
The goal of the current investigation was to better understand opioid response patterns to multiple experimental pain modalities and the influence that opioid type and individual characteristics had on these responses. This was accomplished by assessing the analgesic effects of morphine and butorphanol in response to thermal, pressure and ischemic pain tasks in healthy adults.
I see a problem here right away: they are using “healthy adults” as subjects. Since we already know that chronic pain changes the brain, there’s no way to know if these results hold true for the pain population.
Factor Structure for Opioid Effect on Experimental Pain
These six factors included:
(1) butorphanol ischemic pain (consisting of butorphanol ischemic threshold, intensity and tolerance);
2) morphine ischemic pain (consisting of morphine ischemic threshold, intensity and tolerance);
3) butorphanol temporal summation (consisting of butorphanol temporal summation at 46, 48 and 50°C);
4) morphine thermal pain (consisting of morphine thermal threshold, tolerance and temporal summation at 46, 48 and 50°C);
5) morphine pressure pain (consisting of morphine pressure pain threshold at the ulna, trapezius and masseter);
6) butorphanol thermal/pressure pain (including butorphanol thermal tolerance, threshold and PPT at the ulna, trapezius and masseter).
Variable Cluster 1
F value P value Baseline pain response:
0.644 .588 Ischemic intensity
1.181 .320 Ischemic unpleasantness
0.851 .469 Heat pain threshold
1.118 .345 Heat pain tolerance
1.249 .295 TS at 46°C
(mean pain rating)
0.773 .512 TS at 48°C
(mean pain rating)
0.774 .528 TS at 50°C
(mean pain rating)
1.481 .224 PPT masseter (kg) 2.7 (0.9) 2.6 (0.8) 2.4 (0.9) 2.4 (0.7) 0.783 .506 PPT ulna (kg) 4.7 (1.7) 4.3 (1.8) 4.0 (1.7) 3.9 (1.1) 0.715 .545 PPT trapezius (kg) 4.7 (1.9) 4.3 (1.7) 3.6 (1.3) 4.2 (1.4) 1.988 .120 Butorphanol side
SSE sedaton 2.33 (1.26) 3.41 (1.07) 3.21 (1.35) 2.95 (1.39) 3.047 0.032 SSE thermoregulation 1.39 (0.63) 2.02 (0.98) 1.83 (0.93) 1.62 (1.35) 1.522 0.213 SSE tingling 1.61 (0.84) 1.53 (0.65) 1.49 (0.68) 1.24 (0.66) 0.481 0.696 SSE dry mouth 1.21 (0.40) 1.72 (0.76) 1.44 (0.48) 1.43 (0.53) 2.786 0.044 SSE dizziness 1.91 (0.98) 2.28 (0.85) 2.21 (0.81) 1.81 (0.77) 1.115 0.347 SSE nausea 1.14 (0.26) 1.40 (0.70) 1.27 (0.42) 1.25 (0.56) 0.838 0.476 SSE motor symptoms 1.27 (0.36) 1.34 (0.49) 1.21 (0.35) 1.33 (0.51) 0.640 0.591 Morphine side effects:
SSE sedation 2.73 (1.25) 2.28 (0.96) 2.65 (1.06) 2.14 (1.15) 1.379 0.253 SSE thermoregulation 1.33 (0.47) 1.44 (0.57) 1.34 (0.38) 1.24 (0.37) 0.533 0.660 SSE tingling 2.24 (0.86) 1.48 (0.62) 1.41 (0.48) 1.33 (0.47) 5.903 0.001 SSE dry mouth 1.48 (0.85) 1.38 (0.59) 1.30 (0.43) 1.38 (0.73) 0.295 0.829 SSE dizzy 1.76 (0.68) 1.56 (0.59) 1.74 (0.70) 1.57 (0.79) 0.738 0.532 SSE nausea 1.21 (0.60) 1.21 (0.39) 1.18 (0.39) 1.29 (0.76) 0.111 0.954 SSE motor symptoms 1.48 (0.90) 1.22 (0.40) 1.16 (0.29) 1.29 (0.49) 1.516 0.215 Psychological measures :
Kohn Reactivity Scale 61.25
1.089 0.357 PILL 94.83
0.125 0.945 Pain Catastrophizing
2.17 (0.93) 3.03 (2.10) 2.62 (2.14) 2.75 (1.33) 0.791 0.501 PANAS (positive affect) 3.70 (0.32) 3.59 (0.58) 3.68 (0.46) 3.47 (0.59 0.522 0.668 PANAS (negative affect) 1.66 (0.62) 1.79 (0.60) 1.63 (0.45) 1.73 (0.49 0.659 0.579
Bu: butorphanol; TS: temporal summation; PPT: pressure pain threshold; SSE: Somatic Side Effect Questionnaire; PILL: Pennebaker Inventory of Limbic Languidness; PANAS: Positive and Negative Affect Scale
We discovered that analgesic effects grouped primarily by pain modality and were specific to either morphine or butorphanol. Categorizing participants based on their response to these six opioid and modality specific factors led to the identification of four subgroups.
Each group had unique analgesic response profiles; three of which were distinguished by substantial analgesic efficacy in response to one opioid on a specific pain modality. Group characteristics across drug response profiles were similar in regards to demographic factors, baseline pain sensitivity and psychological profile with some variation in side effect profiles
These findings indicate that analgesic efficacy in a given individual could be opioid and pain mechanism specific.
The pain modalities used in this study were chosen to capture a broad range of pain characteristics and have been proposed to activate different pan mechanisms
Findings from the current study support the notion that opioids produce varying analgesic effects depending on the pain mechanism stimulated.
This study also demonstrated that morphine and butorphanol, opioids with differing efficacies at the mu and kappa opioid receptors, produce independent effects on different pain mechanisms.
Had the analgesic effects of morphine and butorphanol on ischemic pain been mediated by similar underlying mechanisms, one ischemic analgesic factor would have emerged regardless of opioid. Instead morphine and butorphanol led to distinct ischemic factors, indicating that different mechanisms underlie responses to these two opioids on this modality.
While the antinociceptive effects of morphine and butorphanol predominately differ in their efficacy at the mu opioid receptor, butorphanol’s full agonist effect at the kappa receptor (albeit with low efficacy) does lead to some pharmacological differences between these two opioids. Neural circuits involved in different aspects of pain processing are differentially populated by mu and kappa opioid receptors.
Given that each pain induction method stimulates unique pain mechanisms and neural circuits, opioids with differing activity at the mu and kappa receptors would have differential effects on the various pain modalities.
The fact that each opioid did not produce consistent results on certain pain modalities (ie. butorphanol was not consistently most effective for ischemic pain or morphine for thermal pain) indicates that individual differences in opioid metabolism and efficacy at the mu and kappa receptors interact with characteristics inherent to each neural circuit to modulate opioid efficacy.
Grouping participants on the opioid and pain modality specific factors revealed four distinct drug response profiles.
Three of the profiles stood out due to their exceptional analgesic efficacy produced by one type of opioid on one pain stimulus modality
The four groups characterized by different drug response profiles did not differ on demographic factors (sex, age, or race), psychological profile, or baseline pain sensitivity
These findings indicate that individuals who received high levels of analgesia from butorphanol had a better side effect profile to this drug as compared to morphine.
Recent research indicates that individual pain variability is, in part, genetically controlled and emerging research demonstrates that the same is likely true for analgesic efficacy.
An individual’s genetic profile can affect:
- genes coding for a drug’s molecular binding site,
- genes that regulate drug transport and metabolism, or
- genes that control enzymes responsible for the drug’s pharmacokinetic properties
The current study was carried out in healthy, young adults using experimentally induced pain. This overcomes many of the complexities inherent in clinical pain that likely affects analgesic efficacy, including but not limited to
- neuroplastic changes effecting both opioid receptor modulation and
- pain related neural circuits.
There is currently a lack of evidence indicating whether analgesic response patterns assessed against experimental pain are predictive of analgesic response to clinical pain.
Interestingly, grouping individuals according to their opioid response profiles established that slightly less than half of the individuals demonstrated substantial opioid and pain modality specific analgesic effects. The remaining individuals showed average analgesic efficacy across opioids and pain modalities.
This investigation provides a foundation for understanding patterns of opioid efficacy in varying types of pain. Our findings suggest that opioid response patterns are more complex than originally thought with about half of individuals exhibiting opioid and pain modality specific analgesic response profiles.