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University of Florida | Journal of Undergraduate Research | Volume 13, Issue 3 | Summer 20 12 1 A D emographic C omparison of the Effects of M orphine and Butorphanol on Pupillometry and Reaction Times Ta rik Ksaibati College of Dentistry, University of Florida Identifying demographic differences in opiate drug effects may lead to more effective opiate treatment regimens. While g ender differences have been discovered for pupil reactions race differences have not been fully investigated This double blinded study administered morphine (0.08 mg/kg) butorphanol (0.016 mg/kg) and s aline to healthy volunte ers and a digital automated pupillometer measured the pupil light reflex before medication and twice after at 15min and 65min. A uditory reaction time measurements were taken before and after drug. In order to determine the differential effects of the drug s on pupillometry across different genders and races a series of mixed model A NOVA analyses were run. I t was determined that there was a drug effect : butorphanol produced a stronger drug effect than both morphine and saline. In addition, butorphanol elici ted the strongest effect in African Americans (p < .001), such that maximum pupil diameter decreased more for butorphanol than morphine and more after morphine than saline. Butorphanol was also stronger than saline or morphine in African Americans for simp le reaction time (p < .001) and stronger in all races for complex reaction time (p = .02). No gender differences were found in any measures examined which is consistent with the current literature. Further research is needed on African American physiologica l differences in opioid responses. INTRODUCTION Pain related issues represent the most common reason for which peop le seek health care 1 Opioids, such as morphine, are the most commonly prescrib ed class of drugs for treating moderate to severe pain opioid receptor a gonist. Whereas b utorphanol is a synthetic opioid analgesic exhibiting opioid opioid receptor. Also kn own as Stadol, butorphanol has been found to be very effective at reducing pain, particularly in women, and is often given during labor 2 Both drugs act by stimulating opioid receptors in the central nervous system, thus providing pain relief. These drugs are prescribed intravenously accordi ng to the weight of the patient. H owever, the effects of the drug v ary widely between individuals. In addition to reducing pain, opioids p roduce other biological effects such as mi osis and altered reaction time (RT) Miosis, or constriction of the pupil, is caused by normal light reflex and occurs in response to opioid and opioid receptor agonists 3 T hat opioids induce miosis in humans is w ell documented, but the factors contributing to variations in pupil size and reactivity are not as well studied 4, 5 It has been shown that there is no light reflex change but there is a decrease in pupil size caused b y opioids 6 The pupillary effects of opioids can be observed just four minutes after administration 7 The P upillometer uses a brief retinal light to induce t he pupilla ry light reflex which causes miosis. For this to occur sympathetic activity from the ciliary ganglion is reduced and parasympathetic activity is increased through disin hibition. The leading theory is pupilloconstrictor neurons in the visceral nu clei of the oculomotor nuclear complex increase frequency of discharge in opioid agonists 6, 8 In general opioid induced miosis in the central nervous system is mediated by the parasympathetic nervous system 9 In addi tion to miosis, opioids can affect psychomotor responses, includin g RT I t has been found that opioids do not have a significant effect on RTs or cognitive functioning but impairment does occur in opioid nave individuals 10 In addition, low doses of morphine may improve psychomotor functions by reducing testing anxiety of the participant 11 The overall effects of butorphanol on psychomotor activities have been shown to be greater tha n that of morphine 12 However, morphine has been shown to inhibit higher cognitive functions rather than the simple auditory RT s 13 This paper will analyze the simple auditory RT s task as both are related to race and gender. Identifying the sources of variability in responses to opioids, including the contributions of factors such as age, sex and ethnicity, may help physicians determine a more effective treatment regimen. A common problem in clinical research is recruitment of Non Hispanic White males only, which is not re presentative of the population 14 Gender differences have been shown in pupil reactions (dilation) to pain stimulation but not to opioid administration 15, 16 Whether pupil responses to opioids vary across ethnic groups has not been fully investigated. One aim of this paper is to characterize gender differences in opioid induced miosis.
T ARIK K SAIBATI University of Florida | Journal of Undergraduate Research | Volume 13, Issue 3 | Summer 20 12 2 METHODS A total of 171 participants between 18 and 45 years old were included in the study. Participants were healthy and free of any ongoing pain conditions or other serious medical or psychiatric conditions. The RT task was perform ed on the first 100 participants and the pupillometry testing was performed on all volunteers Participants were asked not to consume any caffeine 2 hours before testing and refrain from using any medications 48 hours before testing so as not to complicat e results. It is important to note that this excludes certain populations on certain prescription drugs (e.g. antidepressants) from the study. Each subject participated in four experimental sessions, including one introductory session and three sessions i nvolv ing medication administration. The introductory session familiarize d subjects with testing procedures, thereby reducing novelty effects in subsequent sessions. During this session, a medical doctor also examined each participant to assure protocol eli gibility. In the following three drug sessions (approximately 2 to 3 hours each) participants received one of three drugs in randomized order: butorphanol (0.016 mg/kg), mor phine (0.08 mg/kg), or placebo ( control for nonspecific effects of the medication ) Nurses administering the drug via IV cannula ; experimenters and test subjects were blinded from knowing the drug administered to reduce subjective bias. The NeurOptics PLR (Irvine, CA) digital automated pupillometer was used to measure the pupil light r eflex before and after drug administration. The participant was reclined horizontally and the lights turned off to maintain a constant ambient light for pupillometry. After a moment was 5 second target e blink. As the experimenter centered the pupilometer on the eye, a retinal light shined for 0.8 seconds causing a constriction of the pupil followed by dilation when the light turned off. The parameters mea sured for pupil size were maximum (MAX) and minimum (MIN) pupil size. Parameters measured for pupil reactivity were latency (LAT, time difference, seconds, between light initiation and constriction start), constriction velocity (CV, constriction distance, mm, divided by duration, seconds) These data points that determine pupil size and reactivity were measured in a 3.2 second sequence of video. Also, before and after drug administration, a RT task was performed on the Empirisoft DirectRT v2004 software usi ng a laptop and headphones. The software recorded RT to within one millisecond. The simple RT task involved delivery of an auditory tone, and participants were instructed to press the space bar as soon as they heard the tone. Next, the complex task involve d the participant indicating whether a tone was heard in the left or right ear by pushing the left or right arrow keys with their corresponding left or right hands, respectively. Ten trials of each task were administered. The RT tasks were performed before drug 15 20 minutes post drug administration to look at short term effects and 65 minutes post drug administration to look at long term effects of the drug. RESULTS Data Analysis For gender differences, a series of two (gender) by three (drug condition) mixed model A NOVA analyses compared sex with the three different drugs. In addition a series of three by three mixed model A NOVA analyses compared the three races ( Non Hispanic Whites African American and Hispanic) with the three different drugs (morphi ne, butorphanol, and saline) The mixed model allows inter subject comparisons across sexes and or races as well as within subject comparisons of drug effects across the different sessions. The data presented are mean (and standard deviation) change scores (pre drug value post drug value) for the different pupil responses and RTs Participants The a ge of subjects range d between 18 and 45 with the average age 23 years old. The average morphine dose and butorphanol dose administered to men was 6.5mg and 1. 3mg respectively and to women was 5.2mg and 1.0mg respectively. There was a total of 87 men and 84 women in the study with average BMIs of 25.1 and 23.8 respectively The mean baseline values for pupil diameter and reactivity were consistent with those found in previous studies for a healthy population 5, 17 Pupillometry When analyzing the seven measurements of the pupilometer, this study found that the MAX, LAT, and CV were the most useful in ch aracterizing miosis and the pupil light reflex The means presented in T able 1 and Table 2 are the mean differences of the drug effect on an individual as compared to the pre drug state. In Table 1 N = 81 for the men but N = 65 for women. It should be noted t he high er sample population, N = 108 value for Non Hispanic Whites as compared to N = 21 for African Americans and N = 17 for Hispanics in Table 2.
A D EMOGRAPHIC C OMPARISON OF THE E FFECTS OF M ORPHINE AND B UTORPHANOL University of Florida | Journal of Undergraduate Research | Volume 13, Issue 3 | Summer 20 12 3 Table 1. Post M edication M ale and F emale M ean C hange in P upillometry M easures C ompared to P re Medication Measured Parameters Male N = 81 Female N = 65 Morphine Butorphanol Saline Morphine Butorphanol Saline MAXR 0.676 (0.661) 1.596 (1.072) 0.091 (0.550) 0.774 (0.809) 1.744 (1.172) 0.0862 (0.515) MINR 0.441 (0.454) 0.975 (0.692) 0.082 (0.505) 0.537 (0.567) 1.106 (0.708) 0.091 (0.472) LATR 0.008 (0.091) 0.012 (0.107) 0.013 (0.086) 0.029 (0.131) 0.008 (0.102) 0.007 (0.098) CVR 0.067 (0.813) 0.380 (0.669) 0.034 (0.723) 0.007 (1.089) 0.392 (0.658) 0.005 (0.389) MAXL 0.754 (0.702) 2.169 (1.186) 0.08 1 (0.497) 0.848 (0.599) 2.067 (1.106) 0.112 (0.443) MINL 0.483 (0.452) 1.214 (0.682) 0.084 (0.298) 0.533 (0.462) 1.262 (0.718) 0.134 (0.419) LATL 0.007 (0.097) 0.014 (0.101) 0.005 (0.087) 0.011 (0.090) 0.045 (0.117) 0.006 (0.089) CVL 0.153 (0.5 66) 0.651 (1.079) 0.0212 (0.363) 0.152 (0.393) 0.516 (0.757) 0.053 (0.436) Table 2. Post M edication Non Hispanic White, African American and Hispanic M ean C hange in P upillometry M easures C ompar ed to P re M edication Measured Parameters Non Hispanic White N = 108 African American N = 20 Hispanic N = 17 Morphine Butorphanol Saline Morphine Butorphanol Saline Morphine Butorphanol Saline MAXR 0.711 (0.677) 1.663 (1.081) 0.078 (0.544) 0.895 (0.637) 2.174 (1.101) 0.140 (0.588) 0.538 (1.087) 1.076 (1.124) 0.107 (0.369) MINR 0.450 (0.453) 1.035 (0.703) 0.082 (0.484) 0.610 (0.643) 1.247 (0.736) 0.165 (0.561) 0.531 (0.637) 0.776 (0.579) 0.007 (0.440) LATR 0.015 (0.100) 0.004 (0.111) 0.010 (0.091) 0.024 (0.117) 0.039 (0.070) 0.021 (0.095) 0.0 27 (0.164) 0.042 (0.089) 0 (0.093) CVR 0.124 (0.778) 0.389 (0.625) 0.020 (0.440) 0.001 (0.634) 0.461 (0.669) 0.198 (1.160) 0.453 (1.807) 0.275 (0.885) 0.041 (0.453) MAXL 0.800 (0.592) 2.204 (1.021) 0.072 (0.438) 0.800 (0.980) 2.335 (1.353) 0.356 (0.673) 0.750 (0.650) 1.406 (1.469) 0.079 (0.278) MINL 0.523 (0.410) 1.295 (0.636) 0.102 (0.333) 0.484 (0.565) 1.247 (0.829) 0.300 (0.366) 0..413 (0.591) 0.847 (0.830) 0.114 (0.382) LATL 0.006 (0.096) 0.022 (0.101) 0.004 (0.087) 0.037 (0.100) 0.061 (0.173) 0.002 (0.103) 0.008 (0.073) 0.031 (0.073) 0.026 (0.066) CVL 0.163 (0.515) 0.586 (0.996) 0.036 (0.375) 0.054 (0.563) 0.915 (0.779) 0.083 (0.557) 0.202 (0.257) 0.294 (0.691) 0.034 (0.296) Values for changes in MAX pupil diamet er showed a significant drug effect (p < .001), such that the MAX pupil diameter decreased more for butorphanol than morphine and more for morphine than saline as illustrated in Figure 1 and Figure 2 In a comparison of races, the data showed that African A mericans exhibited a larger decrease in MAX pupil diameter after both morphine and butorphanol than Non Hispanic Whites and Hispanics for both the right (p = .026) and left (p = .018) sides as shown in Figure 2
University of Florida | Journal of Undergraduate Research | Volume 13, Issue 3 | Summer 20 12 4 Figure 1 Mean Chang e in MAX and MIN by Sex and Eye. This figure illustrates the drug effect by sex of: MAXR= right eye maximum pupil diameter (mm), MAXL= left eye maximum pupil diameter (mm), MINR= right eye minimum pupil diameter (mm), MINL= left eye minimum pupil diameter (mm). For both CV and LAT no race effect was found. There were no sex differences found for any of the measurements analyzed as illustrated in Figure 1 for the MAX and MIN values. Figure 2 Mean Change in MAX and MIN by Ra ce and Eye. This figure illustrates the drug effect by sex of: MAXR= right eye maximum pupil diameter (mm), MAXL= left eye maximum pupil diameter (mm), MINR= right eye minimum pupil diameter (mm), MINL= left eye minimum pupil diameter (mm).
A D EMOGRAPHIC C OMPARISON OF THE E FFECTS OF M ORPHINE AND B UTORPHANOL University of Florida | Journal of Undergraduate Research | Volume 13, Issue 3 | Summer 20 12 5 The LAT was found to increase more after butorphanol than morphine or saline but only on the left side. LAT showed a side by drug interaction meaning the drug effect depend s on which eye is being tested (p = .03). Regarding t he CV in Table 1 and Table 2 it is importa nt to note that the negative values indicate a slower constriction velocity after drug. There was a main effect of drug on both the right (p =.0001) and the left (p = .0001) eye for CV. The CV increased more after morphine than saline and more after butorpha nol than morp hine Reaction T ime s Table 3 shows the mean change between pre drug and post drug at 15min and 65min for the different races; the positive values indicate there was an increase in reaction time (milliseconds) post drug. Table 3. Mean Cha nge in Simple and Complex RTs by Drug and Race Non Hispanic White African American Hispanic Variable Change N = 84 Change N = 62 Change N = 11 Change N = 10 Change N = 16 Change N = 9 (15min post drug) (65min post drug) (15min post drug) (65min p ost drug) (15min post drug) (65min post drug) Morphine Simple (ms) 13.4 (35.1) 21.9 (40.2) 24.0 (62.0) 25.1 (29.1) 3.7 (52.9) 26.1 (95.4) Complex (ms) 3.7 (58.3) 15.1 (68.2) 4.4 (80.2) 14.2 (106.0) 8.5 (78.9) 4.8 (57.8) Butorphanol Simple (ms) 50.6 (56.8) 17.1 (57.4) 88.6 (165.5) 81.4 (64.8) 38.4 (50.0) 12.0 (11.3) Complex (ms) 33.2 (91.4) 16.7 (106.1) 38.4 (117.7) 18.6 (166.0) 31.6 (90.1) 1.3 (36.1) Saline Simple (ms) 19.7 (39.2) 13.6 (39.0) 8.5 (33.4) 19.5 (26.4) 14.0 (30.9) 10.0 (30 .0) Complex (ms) 3.7 (86.9) 14.9 (89.5) 13.9 (26.1) 29.2 (85.5) 62.5 (82.1) 1.6 (42.1)
T ARIK K SAIBATI University of Florida | Journal of Undergraduate Research | Volume 13, Issue 3 | Summer 20 12 6 Figure 3 Mean Change in Simple RTs by Race Measured in Milliseconds For simple RT there was a larger increase in time after butorphan ol than after saline or morphine (p < .001). This effect appears to be stronger and longer lasting in African Americans ( Figure 3 ). In the complex RT there was also a larger increase in time after butorphanol than after saline or morphine (p = .02). There we re no gender differences for any RT measures as illustrated in Figure 4 Figure 4 Mean change in s imple RTs by gender measured in m illiseconds
A D EMOGRAPHIC C OMPARISON OF THE E FFECTS OF M ORPHINE AND B UTORPHANOL University of Florida | Journal of Undergraduate Research | Volume 13, Issue 3 | Summer 20 12 7 DISCUSSION Morphine and butorphanol produced significant effects on pupil respon ses in the study, which is consist ent with the current research literature 13 T he effect of butorphanol was stronger than that of morphine which was in turn stronger than that of saline for MAX pupil diameter However many studies have shown that the psychomotor effects of butorphanol have been stronger which was shown in the RTs but with regards to miosis there has been little difference found 5, 13 Butorpha nol increased RTs for both simple and complex tasks more than morphine or saline. The pupil response is not a measurement to determine pain analgesia; it simply measures the effect the drug has on the pupil light reflex. The pupil response has been used a s a measure of arousal, anxiety, atten tion, mental effort, and stress 15 However, the situation of the participant may have had additional stress arousal and anxiety due to the stressful nature of being in an unfam iliar environment and anticipating pain testing. The introductory testing session and the rest periods before measurements were designed to reduce these elements. Thus, in the present context, pupil responses can be considered an index of the pharmacologic effect of the medication. The lack of gender differences in the pupil analysis or RTs is consistent with current research Our findings show no gender differences in pupil measurements or RTs The data only show that there is no difference in opioid induc ed miosis and RTs between sexes This does not mean there are no sex differences in opioid anal gesia. In a recent review paper of sex differences in response to opioid medications Paller et al. found that women overall are more sensitive to both dosage an d type of opioid receptor medication. The study showed that the extent of sex difference in pain relief varied depending on the type of pain (cold, heat, pressure, electrical etc.) and the type opioid opioid opioid) 16 In addition, women were shown to be more sensitive to the pain relief opioid receptors ; however the drugs used in this study opioid receptors 16 It is clear that t opioid receptors are involved in pupillometry, though it is unclear what the race and gender effects are for each of these receptors. I t would be advantageous to do a study isolating these receptors in dependently and examining sex and r ace effect on pupillometry. When measuring the maximum pupil diameter, African Americans were found to have a greater drug effect to butorphanol and morphine than Non Hispanic Whites and Hispanics This shows there is a race effect when looking at the p upi l light reflex with opioid induced miosis There was also a race effect for African Americans who experienced significantly delayed simple RTs over the entire test period; however sample size was small for African Americans compared to Non Hispanic Whites. Chen et al found that African Americans are generally unde r treated with opioids in comparison to Non Hispanic Whites, though prescription drug abuse is more prevalent in Non Hispanic Whites. These findings were not a result of access to health care, soc ioeconomic class or behaviors; instead the findings were attributed to African Americans experiencing stronger chro nic pain than whites 18 The findings in this study could suggest that the increased drug effect on pupil diameter and RT may appear to healthcare providers as greater pain relief. However, further inves tigation into factors in fluencing opioid prescription by health care providers is needed. It is important to note that only the left eye showed a significant increase in latency time. LAT measurements were the only measurements to exhibit a side by drug interaction meaning the magnitude of the drug effect did depend on what eye was being measured. However, previous studies have found that opioids do not produc e significant changes in the reactivity aspects of miosis such as latency 16 Further most previous studies have not examined potential differences between right and left eyes in opioid clinical research I n most ca ses only the right eye is examined 4, 5 or a distinction is not even made 5, 17 The high sample size of 171 participants gave this clinical s tudy many advantages ; however, all participants did not complete every aspect of testing due to various complications such as scheduling conflicts, unwanted drug reactions (nausea), and testing issues. Only participants with complete data sets were includ ed in the study which decreased the two minority populations significantly for RT data It should also be pointed out that the young average age of the participants (23 years old) does not correspond to the generally older average age of the opioid using population in hospital settings. The data might not be relevant to this older population; further research into age demographics is warranted. One strength of the study was a relatively even distribution of sex ; however race was not as evenly distributed The small sample of Hispanics (N = 17) and African Americans (N = 2 0 ) compared to the large Non Hispanic Whites (N = 108) population is another limiting factor. A more even distribut ion of race should be sought in future studies and may find more significant r esults. However, considering that th e majority of studies examining opioid induced miosis and RT hav e a sample size of less than 20 individuals the results found i n this study remain important Future studies should examine the effects of these drugs in d ifferent dosages and infusion rates on different demographics. Marsch et al. found that infusion rates were not found to influence pupil diameter but higher dosages of opioids were found to decrease diameter. A more recent on pupil constriction was time dependent, not dose dependent H owever this study
T ARIK K SAIBATI University of Florida | Journal of Undergraduate Research | Volume 13, Issue 3 | Summer 20 12 8 used much higher dosages which suggest s there may be a ceiling effect of physiological efficacy in pupil constriction 17 Women are sugg ested to be more sensitive at higher dosages of opioids than men in analgesia Therefore, there may be a papillary or RT effect ; further research is needed 16 Th ese data will be added to the know ledge base of opiate s tudies in hopes to better characterize the physiological and psychomotor effects on different demographics and how they respond to pain. Though only race and gender w ere analyzed the results will prove u seful for future research, especially in the much ne eded area of race. ACKNOWLEDGMENTS I would like to acknowledge my research mentor Dr. Roger Fillingim, Toni Glover, Dr. Christopher King, Tara Keels and Terry Weber for all their support and guidance through this research project. REFERENCE S 1. Turk Dennis C, Melzack Ronald. The measurement of pain and the assessment of people experiencing pain. In: Turk Dennis C, Melzack Ronald, editor. Handbook of pain assessment. 2nd ed. New York: Guilford Press; 2001. 2. Vogelsang J, Hayes SR. Butorpha nol tartrate (stadol): A review. J Post Anesth Nurs 1991 Apr;6(2):129 35. 3. Marsch LA, Bickel WK, Badger GJ, Rathmell JP, Swedberg MD, Jonzon B, Norsten Hoog C. Effects of infusion rate of intravenously administered morphine on physiological, psychomotor, and self reported measures in humans. J Pharmacol Exp Ther 2001 Dec;299(3):1056 65. 4. Zacny JP. Morphine responses in humans: A retrospective analysis of sex differences. Drug Alcohol Depend 2001 Jun 1;63(1):23 8. 5. Zacny JP, Lichtor JL, Flemming D, Coa lson DW, Thompson WK. A dose response analysis of the subjective, psychomotor and physiological effects of intravenous morphine in healthy volunteers. J Pharmacol Exp Ther 1994 Jan;268(1):1 9. 6. Larson MD. Mechanism of opioid induced pupillary effects. Cl in Neurophysiol 2008 Jun;119(6):1358 64. 7. Miller CD, Asbury AJ, Brown JH. Pupillary effects of alfentanil and morphine. Br J Anaesth 1990 Sep;65(3):415 7. 8. Lee HK, Wang SC. Mechanism of morphine induced miosis in the dog. J Pharmacol Exp Ther 1975 Feb; 192(2):415 31. 9. Murray RB, Adler MW, Korczyn AD. The pupillary effects of opioids. Life Sci 1983 Aug 8;33(6):495 509. 10. Ersek M, Cherrier MM, Overman SS, Irving GA. The cognitive effects of opioids. Pain Manag Nurs 2004 Jun;5(2):75 93. 11. Hanks GW, O' Neill WM, Simpson P, Wesnes K. The cognitive and psychomotor effects of opioid analgesics. II. A randomized controlled trial of single doses of morphine, lorazepam and placebo in healthy subjects. Eur J Clin Pharmacol 1995;48(6):455 60. 12. Walker DJ, Zacn y JP, Galva KE, Lichtor JL. Subjective, psychomotor, and physiological effects of cumulative doses of mixed action opioids in healthy volunteers. Psychopharmacology (Berl) 2001 Jun;155(4):362 71. 13. Zacny JP, Conley K, Galinkin J. Compa ring the subjective, psychomotor and physiological effects of intravenous buprenorphine and morphine in healthy volunteers. J Pharmacol Exp Ther 1997 Sep;282(3):1187 97. 14. Mosenifar Z. Population issues in clinical trials. Proc Am Thorac Soc 2007 May;4(2 ):185,7; discussion 187 8. 15. Ellermeier W, Westphal W. Gender differences in pain ratings and pupil reactions to painful pressure stimuli. Pain 1995 Jun;61(3):435 9. 16. Paller CJ, Campbell CM, Edwards RR, Dobs AS. Sex based differences in pain perceptio n and treatment. Pain Med 2009 Mar;10(2):289 99. 17. Walsh SL, Chausmer AE, Strain EC, Bigelow GE. Evaluation of the mu and kappa opioid actions of butorphanol in humans through differential naltrexone blockade. Psychopharmacology (Berl) 2008 Jan;196(1):14 3 55. 18. Chen I, Kurz J, Pasanen M, Faselis C, Panda M, Staton LJ, O'Rorke J, Menon M, Genao I, Wood J, Mechaber AJ, Rosenberg E, Carey T, Calleson D, Cykert S. Racial differences in opioid use for chronic nonmalignant pain. J Gen Intern Med 2005 Jul;20(7 ):593 8.