Pain Perception and Serum Beta-Endorphin in Trauma Patients
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Pain Perception and Serum Beta-Endorphinin Trauma Patients
LAWSON BERNSTEIN, M.D., PAMELA D. GARZONE, PH.D.
THOMAS RUDY, PH.D., BRUCE KRAMER, M.D.
DWIGHT STIFF, PH.D., ANDREW PEITZMAN, M.D.
Acute traumatic injury engenders the production ofbeta-endorphin (BE) and otherendogenous opioids. Elevated BE concentration putatively correlates with pain perception in trauma patients. The authors examined traumatic injury severity, pain perception. and BE concentration in patients admitted to an urban trauma center. Briefrating instruments for pain and unpleasantness were administered. and blood wasdrawn for BE analysis in 48 trauma admissions and 33 age-. gender-. and racematched control subjects for comparison. The authors found no correlation betweenseverity ofpain perception and BE. but a significant correlation was found betweenBE and patient body weight (P< 0.05), physician pain rating (P < 0.01), and InjurySeverity Score (P < 0.001). The results suggest that past findings associating traumapain perception and BE concentration are spurious.
(Psychosomatics 1995; 36:276-284)
T raumatic injury is a pervasive medical andpublic health problem that costs billions of
health care dollars each year.' Concomitantwith injury is the perception of pain, with andwithout tissue damage.2 A great variability inpain response is common in persons with similar injuries, and it appears that both physiologicand psychologic factors play important roles in
Received March 12. 1993; revised May 7. 1993; accepted June 23. 1993. From the Department of Psychiatry.Consultation Psychiatry Division. the Department of Pharmacy and Therapeutics. the Department of Anesthesiologyand Pain Institute. the Department ofCrilical Care Medicine.the Department of Surgery. Trauma Surgery Division. andGenetech. Inc.; all are at the University of Pillsburgh Medical Center and Western Psychiatric Institute and Clinic(WPIC), Pillsburgh. PA. Address reprint requests to Dr.Bernstein. WPIC. 3811 O'Hara Street. Sle. 102. Pinsburgh.PA 15213.
Copyrighl © 1995 The Academy of PsychosomaticMedicine.
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pain modulation.2-4 Unmodulated pain has beenshown to have a deleterious effect on patientsurgical outcome, including greater postoperative morbidity and increased mortality whencompared with more adequately treated controlsubjects.5-8
Psychiatric sequelae, including mood andanxiety disorders, have been noted in patientswith traumatic injury and severe pain.9-17 Research and clinical experience suggest that earlyaggressive pain treatment correlates with betteranalgesic efficacy's and later psychiatric outcome,IO·15-17 yet adequate pain assessment andtreatment remains an ongoing issue of debate inmanaging the trauma patient. 19.20
Acute traumatic injury engenders a varietyof physiologic changes involving the cardiovascular, endocrine, and inflammatory systems.6
Concomitant with the injury are the phenomena of pain and "stress-induced analgesia"21and neuroendocrine modulation of pain percep-
PSYCHOSOMATICS
tion. Tissue production of corticotropin-releasing hormone (CRH)-like substances after injuryappear to mediate stress-induced analgesiathrough increased hypothalamic production ofproopiomelanocortinin, the precursor proteinof adrenocorticotropin and beta-endorphin(BE).21.22 BE, along with other endogenousopioids, attenuates the neurophysiologic response to acute pain. 23-25 Cardiovascular collapse associated with hypotension parallels theacute rise in BE levels26 and can be attenuatedby opioid antagonists such as naloxone.26-31 BEreturns to baseline or subnormal levels after 5to 14 days, and BE has been correlated withincreased pain behaviors in the rat trauma-injury mode I.32
Transient elevation of BE also accompanies ethanol use,3] a frequent comorbid condition with traumatic injury.34-36 In addition,obese people have greater baseline serum concentrations of BE36-38 compared with normalweight people.
BE serum concentrations have been used asa measure of acute pain and a measure of theefficacy of opiate analgesia in postoperative,39cancer,40.41 and pediatric bum patients.42.43 It hasbeen postulated that unmedicated acute injurypain proportionally correlates with increasedBE concentration. However, studies with human and animal models of pain and opiate efficacy have presented varying and inconclusiveresults40.42-44 and have not controlled for otherphysiologic variables associated with BE production.
MATERIALS AND METHODS
This study was conducted in 1992 at the University of Pittsburgh Trauma Center, wherethere are approximately 2,000 adult trauma injury evaluations a year. Forty-eight consecutivepatients admitted for trauma who met the inclusion criteria (systolic blood pressure [SBP]greater than 90 mmHg and Glasgow ComaScale [GCS] score greater than 8) were evaluated. The GCS is a standardized continuousrating scale to assess consciousness level, andit is an accepted measure of mental status ab-
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normality in the acute trauma setting.45 A GCSof 8 or higher generally indicates that a patientis able to follow commands and respond appropriately to questions. An SBP of less than 90mmHg is accepted as clinical evidence of significant hypotension in the trauma patient,46 andfor the purpose of this study we used this standard as the measure for hypotension. The lowestdocumented SBP was the standard used to determine significant hypotension. Patients givenmedication in the field or with significant prehospital hypotension were excluded from thestudy.
After initial evaluation by the trauma team,but before treatment, the patients who met theprotocol criteria were asked by the principalinvestigator/coinvestigator (LB/BK) to participate in a brief (I-minute) pain assessment andto permit the investigator to withdraw a 5-ccaliquot of blood for BE measurement. Withincreasing evidence that two dimensions ofacute pain should be assessed,47 two Visual Analog Scales (VAS)-one for pain intensity andone for pain unpleasantness-were administered to the patient. A blinded physician VASco-rating was done by the investigator (LB/BK)before patient recruitment or review of clinicaldata, but after blood had been drawn for BEanalysis. The physician-raters relied on assessment of pain behaviors (e.g., grimacing) to derive VAS scores. The VAS is a well-validatedpain rating instrument used in a number of painstudies in trauma patients.48.49., The patientmarks a point on a 10-cm line that best reflectshis or her current level of pain. The left side ofthe line is marked "no pain" and the right "extreme pain." The score (0-10) is measured bythe distance in centimeters from the extreme leftof the line to the patient's mark.50
The 5-cc aliquot of blood drawn at admission was placed in a vacutainer tube containingethylenediaminetetracetic acid and aprotininand immediately placed on ice. The time ofsample collection was recorded. Blood sampleswere decanted and the plasma frozen untilanalysis for BE. The elapsed time from admission to assessment was approximately 10 minutes in most cases. In most instances, when it
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Pain and Serum Beta-Endorphin
did not interfere with clinical care (i.e., criticalillness, "stat" transfer to intensive care unit,etc.), informed consent was obtained before theinterview. Otherwise, informed consent was obtained after the patient was stabilized medically.This protocol was approved by the Universityof Pittsburgh Medical Center Institutional Review Board and is in accordance with its established guidelines on the treatment of humansubjects.
The medical record was screened for demographic data such as age, gender, and weight. Inaddition, the Injury Severity Score (ISS)51 wasrecorded. The ISS is a point-system test thatyields a hierarchical rating for various injurytypes, thus allowing for comparison of injuryseverity between patients with different traumas. At admission, blood alcohol level and toxicology screen results were recorded and scoredcategorically (positive/negative) for the primary analysis.
Thirty-three healthy volunteers served asthe control group. They were recruited througha local newspaper advertisement that asked forsubjects without an acute or chronic illness orcurrently on prescription medication. Patientswere also interviewed as to health status beforestudy entry. These healthy and unmedicatedvolunteers, matched to the trauma patients forage, gender, height, and race, also had a 5-ccaliquot of blood drawn, and the VAS was administered to them in the manner previouslydescribed. This ensured that both groups experienced the minor trauma of phlebotomy priorto VAS rating. These blood samples were centrifuged, plasma decanted, and frozen untilassay.
BETA-ENDORPHIN ASSAY PROCEDURE
Plasma concentrations of immunoreactive BE(, 25I_BE) were determined with a commerciallyavailable radioimmunoassay (RIA) kit (INCSTAR Corp., Stillwater, MN). Blood sampleswere collected as described. The samples wereimmediately centrifuged for 15 minutes at760 x g (40 C), and the serum was removed andstored at -850 C until assayed. The RIA used
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the double-antibody technique. BE was extracted from plasma by passage through a column containing anti-BE-coated sepharoseparticles. Bound BE was subsequently elutedfrom the column and incubated with beta-endorphin antiserum, followed by '25I_BE. Phaseseparation was done with a preprecipitatedcomplex of second antibody and carrier. Allsamples and standards were subsequentlycounted in an 1272 CliniGamma gammacounter with a calculation method of %B/Bo(percent bound/free) vs. log concentration.
The antibody to BE has a cross reactivityof 100% to human BE, less than 5% cross-reactivity to B-lipotropin, and essentially no crossreactivity to other peptides or proteins such asdynorphin, enkephalin, adrenocorticotropichormone, luteinizing hormone, or folliclestimulating hormone. The range of quantitationfor the assay is 5-80 pmol/L, with the limit ofdetection being approximately 3 pmol/L. Theintra-assay coefficient of variation (CV) is< 10% , except at the limit of quantitation,which has a CV of 13.7%. Concentration valuesfor quality control samples analyzed with eachset of study samples consistently fell within therange specified for each kit. In addition, thecalculated value for the control group was always within 10% of its theoretical value.
In addition to performing the standard validation described, several other factors andplasma constituents were evaluated for theireffects on the accurate determination of plasmaBE. Because trauma patients could potentiallyhave had their injury precipitated through theuse of ethanol or other drugs of abuse, it was ofinterest to evaluate the effects of these agentson the assay. In addition, these subjects mayalso have experienced posttraumatic metabolicdisturbances that produced changes in plasmacomponents such as albumin and alpha-I acidglycoprotein (AAG), as well as changes inplasma pH, which could potentially affect accurate analysis of BE. These factors also requiredevaluation of their possible effects on the assay.To I-rnl aliquots of control plasma was added100 IJ.g each of morphine, o-amphetamine, cocaine, and tetrahydrocannabinol. This concen-
PSYCHOSOMATICS
Bernstein et al.
TABLE 1. Patient descriptive statistics for predictors of posttrauma beta-endorphinconcentration
Comparison of Beta-EndorphinConcentration in Trauma
Patients and Control Subjects
The control subjects had significantlylower posttrauma PBEC than the patients (P <0.001, Table I). The mean PBEC for the control subjects and patients was $ 5 pmol/L(SO = 1.25, range =$ 5-8.6 pmol/L) and16.39 pmollL (SO =16.83, range =5 $ -66.2pmollL), respectively. However, because the
36.68 (SO =15.37), respectively, served ascontrol subjects. The control group was notsignificantly different from the patient groupwith respect to age, gender, race, and height.The patients and control subjects differed as toweight: the patients mean weight was 170.26,Ib (SO = 37.43), compared with the controlgroup's weight of 147.33 Ib (SO = 23.48) (P <0.(01).
DescriptiveStatisticVariable
Statistical Methods·
tration is well above that reported to cause toxicity and the level that would be expected tooccur after extensive abuse of these agents.Ethanol (2.5 fll) was added to a plasma sampleto give a concentration of 200 mg percent. Fortymg of albumin was added to plasma containing4.5 g/dL to give a final concentration of8.5 g/dL, whereas 8.2 mg of AAG was added toplasma containing 7.8 mg to give a final concentration of 160 mg/dL. Plasma pH was adjusted by adding 25 fll of either I mollLhydrochloric acid or I mollL sodium hydroxideto a I ml sample to give final pH values of6.5 and 9.4, respectively.
None of these perturbations produced a statistically significant effect on the measured concentration of BE in a control subject's plasmasample. In addition, a 2-cycle freeze thaw of aplasma sample and allowing it to sit at roomtemperature for up to 2 hours was without effect. The results of these validation studiesprove that the BE assay is sensitive and specificand that is also not easily influenced by severalphysiological factors that may be present intrauma patients.
38.7 ± 17.1
170.3 ± 37.4Chi-square tests and analysis of variancewere used to evaluate significant differencesbetween the control and patient samples. Linearregression analyses and Pearson correlationswere used to determine the association betweenposttrauma beta-endorphin concentration(PBEC) and selected predictor variables. Partialcorrelations were used to further clarify theassociation between patients' and physicians'pain ratings, injury severity, and PBEC. OnlyP values less than 0.05 were considered statistically significant.
RESULTS
Forty-eight patients, 28 men (mean age = 42.43years, SO =20.21), and 20 women (mean age =34.95, SO = 10.15) completed the study.Thirty-three subjects, 14 men and 19 women,with a mean age of 35.57 (SO =18.73) and
Age. years. mean ± SO
Weight. lbs. mean ± SOGender of patients, n
Men
Women
Type of trauma, %
Head injury
FallMotor vehicle accident
Assault
Amputation
Penetrating assault
Alcohol on breath. 0/0
Alcohol in blood
Loss of consciousness. 0/0Patient pain severity rating (0-10).
mean±SO
Patient pain unpleasantness rating <G-IO).mean ±SO
Physician pain unpleasantness rating (0-10)mean±SO
Injury Severity Scoremean±SO
28
20
8.3
8.3
68.38.3
4.2
2.1
10.416.2
28.3
4.2± 2.6
5.8 ± 3.1
4.6± 2.7
4.4 ± 4.2
VOLUME 36 • NUMBER 3 • MAY - JUNE 1995 279
Pain and Serum Beta-Endorphin
weight of the subjects was found to be significantly correlated with PBEC (r = 0.385,P <0.00 I), and because the control groupweighed significantly less than the patientgroup (P < 0.0 I), an analysis of covariance wasdone to test whether significant PBEC groupdifferences remained after statistically controlling for body weight. This analysis indicated thepatient group still had a significantly higherPBEC than the control subjects after covaryingfor body weight (P < 0.01).
Predictors of PosttraumaBeta-Endorphin Concentration
Twelve variables were hypothesized as being potential predictors of posttrauma PBEC.The variables and mean values are also presented in Table I. Separate regression analyseswere computed to evaluate the contribution ofthese 12 variables to PBEC. The results of theregression analyses are presented in Table 2.
As shown in Table 2, the patient's weight,the physician's rating of the patient's pain se-
TABLE 2. Regression results testing predictorsof posttrauma beta·endorphine con·centration (PBEC)
StandardizedVariable Beta" rZb p
Age -0.114 0.013 NS
Weighl of palienls 0.318 0.101 <0.05
Trauma result of a -0.070 0.005 NShead injury
Alcohol on brealh -0.103 0.011 NS
Alcohol in blood -0.190 0.037 NS
Loss of consciousness 0.072 0.005 NS
Palienl pain severity 0.237 0.056 NSraling
Physician pain severily 0.394 0.155 <0.01raling
Physician pain unpleasanlness 0.197 0.0039 NSraling
Injury Severily Score 0.632 0.399 <0.001
Note: NS =nOI significan!."Measure is analogous 10 Pearson correlalions."The proporlion of variance in PBEC Ihal can be
explained by each of Ihe predictor variables(1.0 would indicale perfeci prediclion).
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verity, and the ISS were significantly associatedwith PBEC. These three significant predictorsaccounted for 51.3% of the variance in PBEC(P < 0.001). The patients' pain severity or unpleasantness ratings were not significant predictors of PBEC.
Additional analyses were done to furtherclarify the apparent discrepancy between thepatients' and physicians' pain ratings. Results ofthese are presented in Table 3. As shown inTable 3, the patients' and physicians' pain severity and pain unpleasantness were significantly correlated. However, the physicians', butnot the patients' ,pain severity and pain unpleasantness ratings were significantly associatedwith the ISS. Controlling for the significantassociation between the ISS and pain severityscore, the partial correlation between the physicians' rating of pain severity and PBEC wasnot statistically significant (r =0.12, P =0.39).
DISCUSSION
The production of BE in the acute trauma setting is a complex physiologic event. In addition,other psychologic and pharmacologic variablesalso affect the BE response to injury. Previoushuman studies examining the BE-acute painrelationship have not taken this multivariatepathophysiologic approach. In this study, anassociation between patient pain intensityand/or pain unpleasantness perceptions and elevated BE could not be demonstrated.
As noted, local tissue response to injuryproduces CRH-like factors that augment physiologic secretion of BE from the hypothalamusand the adrenals. The positive correlation between BE and body weight may be attributableto increased local tissue response to injury(more soft tissue to injure), augmented hypothalamic response to CRH, or increased adrenalproduction of BE in heavier persons. Becausethe hypothalamic-pituitary-adrenal axis may react differently in the obese,36 and because BEconcentrations are generally higher in the overweight as compared with normal weight persons,37.38 these factors would seem a likelyexplanation. Likewise, obesity itself could be a
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Bernstein et al.
TABLE 3. Pearson correlations among pain ratings and Injury Severity Scores
Measure PPS PUP MDPS MDUP ISS
Patient pain severity (PPS) 1.00
Patient unpleasantness (PUP) 0.27 1.00Physician pain severity (MDPS) 0.54- 0.19 1.00
Physician unpleasantness (MDUP) 0.38- 0.46- 0.54- 1.00Injury Severity Score (ISS) 0.27 0.02 0.46- 0.41- 1.00
-P<O.OI.
risk factor for greater tissue damage caused byblunt trauma, because there is a relationshipbetween force of impact and weight. However,neither of these conclusions can be substantiated by our study.
When weight was removed as a potentialconfound, the positive correlation between ISSand BE remained, underscoring the robust relationship between the two. This relationship isconsistent with the role of tissue trauma as theprimary injury-associated variable responsiblefor elevated BE in the trauma patients vs. control subjects. Contrary to other studies, we didnot find a positive association between alcoholand elevated BE concentration, although thiseffect may be undetectable when compared tothe overwhelming stimulus of tissue injury.
Almost 50% of the variance in BE remainsunexplained in this sample, highlighting thecomplexity of BE production. The influence ofalcohol and other factors that affect BE (e.g.,head trauma, loss ofconsciousness) are difficultto separate from the cascade of physiologicevents associated with the neurohormonal response to acute injury.52 No correlation wasfound between the presence of opiates (11.4%of the sample), cocaine (18%), or marijuana( 17%) in serum toxicologies and elevated patient BE. In addition, the effect of chronic vs.acute ethanol and illicit substance use is notquantifiable from this study. Although six casesexperienced transient loss of consciousness atthe scene, none had significantly elevatedPBEC levels. The presence of premorbid significant gastrointestinal (10.4%) or cardiac disease (14.6%) in patients did not correlate withchanges in BE, nor did the presence of current
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prescription drug use (35.3%). Other medicaldiagnoses or illicit substance effects could notbe assessed because of the low presence ofthese in the sample. These other conditionsmay be related to perturbations in BE physiology or premorbid pain experience, which couldaffect acute injury BE response and/or painperception.
The finding of a lack of association between patient pain/unpleasantness and BE contrasts with the studies cited before. Past studieshave suggested that elevated BE is a marker forpain39 and associated with pain perceptions.4J
One hypothesis suggests that elevated BE isassociated with undertreated acute or chronicpain42 and that adequate analgesia is reflectedin normalization of BE levels. Another hypothesis suggests that BE itself has autonomousanalgesic properties40 that modulate the efferentlimb of cutaneous and possibly visceral painperception. Thus, BE levels, either elevated ordepressed, should be positively or inversely related to pain severity perception. Both hypotheses require assumptions as to cause and effectand impute mechanistic connections wherenone may exist.
This study assumes that peripheral measurement of BE reflects central nervous system(CNS) levels of the hormone. It is possible thatthere is a dissociated response between CNSand peripheral production of BE and that different physiological compartments reflect this inequality. Acute CNS production of BE maysignificantly lag behind that of the adrenalgland. Moreover, the ependymal barrier between the brain and the systemic circulation isdiscontinuous. One prominent locus of dis-
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Pain and Serum Beta-Endorphin
continuity is the hypothalamic-pituitary stalk.This suggests that peripheral measurements ofBE may reflect some percentage of centrallyproduced hormone, although the total amountis not known. A dissociated response is difficultto document, however, and requires simultaneous cerebrospinal fluid and serum assays. Studies simultaneously sampling peripheral andcentral BE concentrations are inconsistent indocumenting any correlation between thetwO. 39.43.52-54
An interesting and potentially importantfinding from this study is the significant correlation between physician-rated pain/unpleasantness assessment and ISS. These findingssuggest that the physicians' ratings of pain severity were determined, in part, by their assessment of the degree of trauma present, followedby an inference about how much pain the patient "should be" experiencing. based on behavioral observations (e.g., facial grimacing). Thisreplicates and extends previous findings fromthe nontrauma literature indicating that physicians have great difficulty in estimating patients' pain from the physical examination.55
.56
In addition, these findings underscore the complex relationship between injury and pain,which may encompass psychologic and situational responses idiosyncratic to the patient.
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CONCLUSION
Assessment and management of acute injurypain remains a difficult clinical issue. Our studyhighlights the problems inherent in correlatingpain assessment to a single BE assay and elucidates other confounding physiologic mechanisms that affect BE production. It alsodemonstrates that physician pain assessmentmay overlap only slightly with the patient'sexperience and may rely excessively on injuryassessment alone.
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