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. Author manuscript; available in PMC: 2022 May 27.
Published in final edited form as: Alcohol Clin Exp Res. 2010 May 21;34(8):1433–1441. doi: 10.1111/j.1530-0277.2010.01228.x

Analgesic Effects of Ethanol Are Influenced by Family History of Alcoholism and Neuroticism

Elizabeth Ralevski 1, Albert Perrino 2,3, Gregory Acampora 4, Julia Koretski 5, Diana Limoncelli 6, Ismene Petrakis 7
PMCID: PMC9136640  NIHMSID: NIHMS1801698  PMID: 20497133

Abstract

Background:

Although personality factors and family history of substance abuse influence how individuals experience pain and respond to analgesics, the combined effects of those factors have not been extensively studied. The objective of this study was to consider the possible role of personality trait of neuroticism and family history of alcoholism on the experience of pain and their role in the analgesic response to an ethanol challenge.

Methods:

Forty-eight healthy subjects participated in this study; thirty-one had a positive family history of alcoholism (FHP), seventeen had a negative family history of alcoholism (FHN). They were also categorized based on their neuroticism (N) scores (low N = 28, and high N = 20). This was a double-blind, placebo-controlled, randomized, within-subject design study of intravenous administration of three doses of ethanol. The testing consisted of 3 separate test days scheduled at least 3 days apart. Test days included a placebo day (saline solution), low-exposure ethanol day (targeted breathalyzer = 0.040 g/dl), and high-exposure ethanol day (targeted breathalyzer = 0.100 g/dl). Noxious electrical stimulation and pain assessments were performed prior to start of infusion and at the 60-minute infusion mark.

Results:

The analgesic effect of ethanol was mediated by an interaction between the personality trait of neuroticism and family history. Individuals with family history of alcoholism and high N scores reported significantly more analgesia on low dose of ethanol than those with low N scores. There was no difference in the analgesic response to ethanol among FHNs with low and high N scores.

Conclusion:

These findings support the conclusion that neuroticism and family history of alcoholism both influence the analgesic response of alcohol. Individuals with high N scores and FHP have the strongest response to ethanol analgesia particularly on the low exposure to alcohol.

Keywords: Ethanol, Analgesia, Pain, Neuroticism, Family History of Alcoholism

There are large individual differences in pain sensitivity, pain tolerance, and response to analgesia. Although it has long been known that pain is moderated by physical, psychological, cognitive, and cultural factors (Melzack and Wall, 1965), the relative contributions of each and their interactions remain complex and unclear. Some factors that have been shown to influence pain sensitivity and response to analgesia, such as gender, medical or psychiatric history, have been explored more fully, while others, such as personality factors, history of substance abuse and family history of substance abuse, have received less attention. Consistent with previous research, our group has recently shown that ethanol has analgesic properties in healthy subjects with no family history of alcoholism (Perrino et al., 2008). We wished to further test whether family history of alcoholism and personality traits play a role in the experience of pain and in the analgesic response.

PAIN RESPONSE

Personality traits are considered one of the most important moderators of human behavior, and personality theorists have long argued that personality traits exert a strong influence on pain sensitivity and tolerance (Eysenck, 1967; Weisberg and Keefe, 1999). Eysenck (1981) was the first to outline a biological model of personality with three basic dimensions: neuroticism, introversion/extraversion, and psychoticism. Strong positive correlations have been found between neuroticism (N) in Eysenck’s model and the “harm avoidance dimension” (HA) (Corr et al., 1995; Kumari et al., 1996) described by Cloninger (Cloninger, 1986). Neuroticism is also considered one of the main dimensions of personality in the five-factor model of personality proposed by Costa and McCrae (Costa and McCrae, 1992), and there is a strong relationship between N as measured by both the five-factor model and Eysenck’s model (Costa and McCrae, 1995).

Individuals with high N scores tend to report more somatic complaints (Costa and McCrae, 1987; Watson and Pennebaker, 1989), and this trait seems to be related to the development of physical symptoms and medical conditions related to systemic pain (e.g., joint pain, tension headache, migraine) (Turk-Charles et al., 2008). Among healthy individuals, there is also some evidence from cortical processing studies (using evoked potential studies and magnetic resonance imaging or MRI) that individuals with high N scores process painful stimulation differently than those with low N (Kumari et al., 2007; Vossen et al., 2006).

Among patients with chronic pain, those with high N scores may have a lower pain threshold and greater pain sensitivity (Granges and Littlejohn, 1993; Wilhelmsen, 2005); they report that the pain is more unpleasant but not more intense (Affleck et al., 1992; BenDebba et al., 1997; Harkins et al., 1989; Wade et al., 1992). Laboratory studies with healthy individuals show that those with high harm avoidance (HA) scores (strongly related to N) had a lower pain tolerance for cold and were more sensitive to heat in one study (Kim et al., 2004) and had a heightened pain response using a cold presser test in another study (Pud et al., 2004).

The relationship between pain and alcohol use is complex and multifaceted. Extensive alcohol use may alter or damage opioid and dopamine function responsible for pain modulation (Cowen et al., 2004; Fields and Basbaum, 1999; Vanderah et al., 2001). Therefore, differences in pain tolerance and threshold would be expected based on individual drinking history. For example, sober alcoholics have been found to be more sensitive to pain than nonalcoholic controls (Brown and Cutter, 1977; Petrie, 1978), and current alcoholics report greater sensitivity to pain than individuals who do not have problems with alcohol (Askay et al., 2009). Also, there is a strong positive relationship between chronic pain and substance dependence (Rosenblum et al., 2003) that may be interpreted as a form of “self-medication.” Individuals classified as problem drinkers report more pain and are more likely to use alcohol to cope with pain than nonproblem drinkers (Brennan et al., 2005). A large epidemiological study found that 25–28% of the men in the sample reported self-medicating pain with alcohol (Riley and King, 2009). Others have argued that alcohol use and pain are two manifestations linked to a common neurobiological alteration in glutamate response. The common mechanism hypothesis is supported by findings showing that patients with chronic pain have higher rates (38–44%) of family members with alcohol use disorder than the general population (Goldberg et al., 1999; Katon et al., 1985). The notion that alcohol use and pain have common neurobiological basis also extends to those healthy individuals at risk to develop alcoholism because those with positive family history of alcoholism (FHP) have been shown to be more sensitive to pain using aversive electrical stimulation than individuals with negative family history of alcoholism (FHN) (Stewart et al., 1995). They also have a significantly stronger cardiovascular response to a painful stimulus than healthy controls without family history of alcoholism (Finn and Pihl, 1988).

RESPONSE TO ANALGESICS

Another way to understand pain mechanisms is to evaluate the response to agents that alleviate pain. Personality factors, such as N, personal history of substance abuse, as well as a family history of substance use, are factors that have been shown to influence analgesic response. Most research that evaluates factors that influence analgesic response examines the response to opiates and morphine. High levels of N predict a weak response to analgesia (morphine) and a strong response to placebo among pain sufferers (Wasan et al., 2005). In contrast to patients, healthy individuals with high HA scores reported greater relief from pain after administration of morphine than those with low HA scores (Pud et al., 2006). Family history of substance use also influences response to opiates (Trafton et al., 2007). Substance users with FHP are more sensitive to methadone treatment than those with FHN.

Ethanol as Analgesic

The analgesic properties of ethanol have been recorded for centuries, although very few controlled studies have been conducted to analyze its ability to suppress pain. It is important to study ethanol as an analgesic agent to understand (i) the influence of substance use on pain mechanisms and (ii) its role in vulnerability for developing alcoholism.

There is also evidence that individuals with family history of alcoholism experience the analgesic effects of ethanol differently than those without family history of alcoholism; family history–positive subjects seem to be more sensitive to the analgesic ethanol effects than healthy controls (Stewart et al., 1995). The response of family history–positive subjects is similar to alcoholics and problem drinkers (Brown and Cutter, 1977). Our group has recently reported that ethanol (BrAc = 0.100 g/dl) has analgesic properties in healthy subjects (Perrino et al., 2008). The above-mentioned findings suggest that the combination of vulnerability to pain in individuals with high N scores and FHP and the response to the analgesic properties of ethanol may impact drinking.

The objective of this study was to consider the possible role of N and family history of alcoholism on: (i) the level at which a participant first reports feeling pain (pain threshold), and the ability of an individual to tolerate pain, which we will refer to as half-maximal pain intensity as it is a subjective report that at least half of a maximal painful intensity is reached and (ii) the analgesic response to an ethanol challenge. We hypothesized that individuals with high N scores and family history of alcoholism will (i) have lower pain threshold, will require less electrical stimulation to reach half-maximal pain intensity and (ii) will report greater pain relief from ethanol.

METHODS

The current study is a secondary analysis of a previously published study designed to examine the analgesic effects of an intravenous ethanol challenge (n = 60) and to compare the pain responses and analgesic effects of ethanol (Perrino et al., 2008). For this study, we selected a subsample of individuals (n = 48); those who also completed a personality assessment. All participants in this study were healthy individuals who were recruited by advertisements placed in local newspapers and postings in the community.

Subjects were male and female participants between the ages of 21 and 30 with no lifetime Axis I disorders (including substance disorders), medically and neurologically healthy and included both FHNs (n = 31), defined as no family history of alcoholism in any first- or second-degree relatives, and FHPs (n = 17), defined as having a biological father and another first- or second-degree biological relative with a history of alcoholism. Family history was formally evaluated by interviewing the subject to obtain the psychiatric status (including substance abuse/dependence, mood disorder, ASPD) of all first- and second-degree biological relatives (including parents) using the family history method (FHAM-Family History Assessment Module) developed by Collaborative Studies on Genetics of Alcoholism. The FHAM is a reliable method for obtaining family history information, and the specificity and the sensitivity of the FHAM for the diagnosis of substance dependence are quite good (Rice et al., 1995).

Participants were excluded if they were alcohol naïve, adoptees with no contact with biological family members, and history of alcoholism in the mother, to exclude the possibility of fetal alcohol exposure. The study was approved by the Human Subject Committees at both Yale University and VA Connecticut Healthcare System, West Haven.

All potential participants signed informed consent and underwent a baseline screening procedure consisting of detailed medical and psychiatric history, physical examination, and laboratory tests. The methods are also described in Perrino and colleagues (Perrino et al., 2008).

Study Design

The study was a double-blind, placebo-controlled, randomized, within-subject design study of intravenous administration of three exposures of ethanol. The testing consisted of 3 separate test days scheduled at least 3 days apart. Test days included a placebo day (saline solution), low-exposure ethanol day (targeted breathalyzer = 0.040 g/dl), and high-exposure ethanol day (targeted breathalyzer = 0.100 g/dl). All testing was carried out in the Biological Studies Unit at the VA Connecticut Healthcare System, West Haven campus.

Instruments

Ethanol Infusion.

Intravenous ethanol infusion was conducted using a well-established and clearly documented “clamp” procedure (O’Connor et al., 1998, 2000; Ramchandani et al., 1999; Subramanian et al., 2002) that is detailed elsewhere (Perrino et al., 2008). The objective is to reach a targeted ethanol concentration [in this case breathalyzers (BrAc = 0.100 g/dl and BrAc = 0.040 g/dl)] in approximately 20 minutes and maintain that concentration level for the following 60 minutes. After the desired BrAc level is reached, the ethanol infusion is “clamped” and maintained at that concentration level (±5 g/dl) for 60 minutes; infusion adjustments are made if necessary. On placebo day, the intravenous (IV) bottles are identical, and the procedure is matched to that of the ethanol infusion days.

Neuroticism Evaluation.

The NEO Personality Inventory was used as a measure of the neuroticism dimension (Costa and McCrae, 1992) and was administered during baseline assessment. The NEO assesses five main domains of personality: neuroticism (N), extraversion, openness, agreeableness, and conscientiousness. The N factor is further divided into six facets measuring anxiety, angry hostility, depression, self-consciousness, impulsiveness, and vulnerability. For the purposes of the analyses, the total N score was dichotomized into high or low N scores. Scores were adjusted for age and gender, and those scoring above the 84th percentile—considered high based on NEO-PI professional manual (Costa and McCrae, 1992)—were placed in the high N group (n = 20), while those scoring below were placed in the low N group (n = 28).

Pain Testing.

Pain testing consisted of noxious electrical stimulation that was administered using a device (Innervator Model NS252; Fisher Payker, East Tamaki, Auckland, New Zealand) that provides electrical current in the form of square wave stimulation in a 830-ms double-rust pattern (two short burst of three stimuli at a frequency of 50 Hz separated by 750 ms). The electrical stimulation was provided by a member of the research team using a peripheral nerve stimulator. The surface gel electrodes of the stimulator were placed one inch apart over the ulnar nerve at the level of the wrist. Starting at 0 mA intervals, the applied current was progressively increased at 10 mA intervals. The intensity of the pain was measured using a Verbal Numeric Scale (VNS) that ranged from 0 = no pain to 10 = worst pain imaginable. The administration of electrical stimulation stopped after subject reported that the pain intensity was 5 or higher on the VNS scale. The score of 5 or higher was selected because it reflects a significant amount of pain without causing great discomfort and avoids the nonlinearity in grading pain intensity that can occur when higher degrees of pain are measured (Hartmannsgruber et al., 1999). Pain was administered at baseline (time = −110) and after ethanol target was reached (time = +30). At each time point, the pain procedure was administered two consecutive times resulting in four values, two baseline measurements and two measurements after ethanol target was reached. The average milliamp of the two measurements at baseline and after ethanol target was reached was used as a single measurement of baseline and a single measurement of pain after ethanol target was reached. Change scores were created by subtracting baseline pain scores from the pain scores after ethanol target was reached for each exposure on each test day. Changed scores from baseline were used for the analysis of the data. The main pain measures included the following. Pain threshold—the lowest milliamp measurement at which the participant reported that they felt pain was used as a measurement of pain threshold. Half-maximal pain intensity—the milliamp measurement reached by electrical stimulation that produced a rating of 5 or higher on the VNS scale was used as a measurement of pain tolerance. This measurement was used as a proxy measurement of the amount of pain tolerated by an individual.

Several levels of medical safeguards were instituted to ensure the safety for all participating subjects. The following steps were followed: (i) the testing facility was covered at all times by the VA Connecticut Healthcare System (VACHS) medical emergency (“Medical Code”) team; (ii) the nurses in the testing facility were all certified in advanced cardiac life support, and two of the three nurses had extensive medical ICU experience; (iii) there was continuous medical and nursing presence throughout the test day; (iv) physician investigators associated with this study were also available during the test days.

Subjective Measures of Ethanol Effects.

To assess the effects of ethanol, a visual analog scale measuring the following affective states was used: buzzed, anxious, irritable, and depressed. Subjects indicated how they felt by drawing a line on a scale from 0 = not at all to 7 = extremely. The visual analog scale was administered at baseline (time = −140), after start of ethanol infusion (time = −10), when ethanol target was reached (time = 0), and during clamp (time = +30). To assess alcohol intoxication, a single-item “number of drinks” scale (NDS) was used. For this item, subjects were asked to indicate the level of drunkenness based on the number of drinks. The NDS was administered three times: at baseline (time = −140), after start of ethanol infusion (time = −10), and after ethanol target was reached (time = 0).

STATISTICAL ANALYSES

For the test of our primary hypothesis, we used mixed effects models to 1) examine the influence of N and family history on pain threshold and half-maximal pain intensity and 2) assess changes in pain over the three different exposure conditions. The primary outcome variables included measures of pain threshold and half-maximal pain intensity. All variables were tested for normality using Kolgomor–Smirnov test. All analyses were performed using 12.0 or higher version of SPSS. The model for the first primary hypothesis included placebo exposure only (BrAc = 0.00 g/dl) as a dependent variable, N (low and high) as a between subject factor, family history (FHP, FHN) as a between subject factor, and one two-way interaction N by family history. The model for our secondary primary hypothesis that examined changes in pain over three different ethanol exposure conditions included ethanol exposure as a within-subject factor (BrAc = 0.00 g/dl, BrAc = 0.04 g/dl, and BrAc = 0.1 g/dl), N (low and high) as a between-subjects factor, family history (FHP, FHN) as a between-subjects factor and their interactions; two-way interactions of exposure by N, exposure by family history, and one three-way interaction exposure by N by family history.

Other analyses included variables of alcohol effects and incorporated breath alcohol levels during infusion, number of drinks, and the VAS mood scores. The average breath alcohol level over the 60-minute clamp procedure on the low- and high-exposure day was calculated to confirm that the amount of alcohol remained constant. To examine the affective changes often attributed to alcohol, mixed effects models were used to examine differences between BrAc = 0.00 g/dl, BrAc = 0.04 g/dl and BrAc = 0.10 g/dl using the VAS scale (feeling buzzed, anxious, irritable, and depressed) and the NDS scale. The model included exposure as a within-subject factor (BrAc = 0.00 g/dl, BrAc = 0.04 g/dl, and BrAc = 0.10 g/dl), time as a within-subject factor (for VAS scale there were four time points, for NDS scale there were three time points), N (low and high) as a between-subjects factor, family history (FHP, FHN) as a between-subjects factor and their interactions; two-way interactions of exposure (or time) by N, exposure (or time) by family history, two three-way interactions exposure (or time) by N by family history, and one four-way interaction exposure by time by N by family history. Bonferroni procedure was used where appropriate to adjust the α level for multiple comparison (VAS scale).

RESULTS

Descriptive Characteristics

The demographic characteristics for all participants are listed in Table 1. The average age of the sample was 23.71 (SD = 2.77), and the majority were Caucasian (33 or 68%). The groups (FHP vs. FHN; High N vs. Low N) did not differ on the total number of drinks consumed within the last month (mean = 19.4, SD = 19.4), years of education (mean = 15.96, SD = 1.9), or age at which they engaged in heavy drinking (mean = 20.1, SD = 1.99). There was a gender difference in this sample with a higher percentage of male participants in the high N group and a lower percentage of male participants in the low N group (68% vs. 32%, respectively, p = 0.000). There were significant differences between those with high and low N scores in the number of total drinking days and age when first started drinking: those with high N scores had significantly more drinking days (high N mean = 8.7, SD = 6.0, low N mean = 5.1, SD = 3.8) (p = 0.005) but had their first drink at a later age than those with low N scores (high N mean = 17.9, SD = 1.1, low N mean = 16.7, SD = 2.3) (p = 0.02). Baseline pain ratings are listed in Table 2. There were no differences between the groups on measures of pain tolerance or pain threshold at baseline on any test day.

Table 1.

Demographic Characteristics

Variables [negative family history of alcoholism (FHN) = 31, positive family history of alcoholism (FHP) = 17] Low Neuroticism means (SE)
N = 28		 High Neuroticism means (SE)
N = 20		 Statistics F Significance (p)
Age FHP 24.71 (1.1) n = 7 23.60 (0.8) n =10 FamHis = 0.41 0.52
FHN 23.38 (0.6) n = 21 23.80 (0.8) n =10 N = 0.15 0.69
FamHisXN = 0.75 0.39
Total drinking days FHP 2.57 (1.8) 7.70 (1.5) FamHis = 3.11 0.08
FHN 5.90 (1.0) 9.70 (1.5) N = 8.7 0.005
FamHisXN = 0.19 0.66
Total number of drinks (last mo) FHP 4.71 (7.2) 21.5 (6.0) FamHis = 2.62 0.11
FHN 20.7 (4.1) 24.8 (6.0) N = 3.07 0.08
FamHisXN = 1.1 0.29
Years of education FHP 16.4 (0.7) 15.6 (0.6) FamHis = 0.05 0.81
FHN 15.6 (0.4) 16.7 (0.6) N = 0.04 0.83
FamHisXN = 2.5 0.12
Age at first drink FHP 15.8 (0.7) 18.0 (0.6) FamHis = 0.65 0.42
FHN 17.0 (0.4) 17.8 (0.6) N = 5.5 0.02
FamHisXN = 1.2 0.26
Age at first heavy drinking FHP 20.2 (1.9) 20.0 (1.8) FamHis = 0.17 0.89
FHN 19.9 (2.3) 20.4 (1.5) N = 0.04 0.84
FamHisXN = 0.22 0.63
Low Neuroticism High Neuroticism
Variables N = 28 N = 20 Statistics χ2 Significance (p)
Gender Male 8 17 14.8 0.000
Female 20 3
Ethnicity White 20 13 3.6 0.45
AA 6 4
Other 2 3
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Bold values indicate p < 0.05.

Table 2.

Baseline Pain Ratings (All Measures in Milliamperes)

Variables [negative family history of alcoholism (FHN) = 31, positive family history of alcoholism (FHP) = 17] Low Neuroticism means (SD)
N = 28		 High Neuroticism means (SD)
N = 20		 Statistics F Significance
Half-maximal pain intensity
 BrAc = 0.00 g/dl FHP 42 (17) n = 7 46 (17) n =10 NS NS
FHN 49 (16) n = 21 49 (12) n =10
 BrAc = 0.04 g/dl FHP 52 (19) 49 (17) NS NS
FHN 50 (15) 46 (17)
 BrAc = 0.10 g/dl FHP 45 (19) 50 (14) NS NS
FHN 49 (17) 48 (13)
Pain threshold (sensitivity)
 BrAc = 0.00 g/dl FHP 15(11) 11 (3) NS NS
FHN 17(11) 13(4)
 BrAc = 0.04 g/dl FHP 17 (12) 14(5) NS NS
FHN 17 (10) 13(4)
 BrAc = 0.10 g/dl FHP 15(7) 13(6) NS NS
FHN 16 (10) 14(7)
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Pain Threshold/Half-Maximal Pain Intensity (Placebo Condition Only)

Our data showed that there were no differences between the groups (N or family history) on measures of pain threshold or half-maximal pain intensity on placebo. Participants reported that they first felt pain around 15 mA (pain threshold), and around 40 mA (half-maximal pain intensity) they reported a rating of pain of 5 or higher. There were no differences in pain threshold or half-maximal pain intensity based on family history of alcoholism.

Response to Ethanol (Ethanol Analgesia)

Overall Response to Ethanol.

The analysis that examined the overall effect of ethanol on pain without the influence of N or family history showed that the increase in ethanol exposure significantly increased the amount of current required to reach half-maximal pain intensity. The findings are very similar to results we reported previously with a larger sample of 60 subjects (Perrino et al., 2008). The change from baseline pain scores was 0.125 (SD = 0.60), −0.17 (SD = 0.85), and −0.42 (SD = 0.91) for placebo, low exposure to ethanol, and high exposure to ethanol, respectively. Ethanol had no significant effect on pain threshold. The change from baseline pain scores was 0.04 (SD = 0.28), −0.06 (SD = 0.43), and −0.06 (SD = 0.72) for placebo, low exposure to ethanol, and high exposure to ethanol, respectively.

Neuroticism and Response to Ethanol.

The data were analyzed to examine whether N alone influenced the effect of ethanol on pain. Neuroticism alone played a role in how individuals reported pain after low exposure to ethanol. For participants with low N scores, there was no significant change in the amount of current required to reach half-maximal pain intensity, while for those with high N scores, there was a significant increase in the amount of current required to reach half-maximal pain intensity (mean change pain scores = 0.07 for low N, and mean change pain scores = −0.50 for high N, p < 0.05). There was no difference between the high and low N group in the amount of current required to reach half-maximal pain intensity on placebo or on high exposure to ethanol. Neuroticism had no effect on pain threshold.

Family History and Response to Ethanol.

We have reported previously on the response to ethanol in a larger sample of 60 individuals (Perrino et al., 2008) comparing individuals with and without family history of alcoholism. The results with this subsample were similar showing that the increase in ethanol exposure significantly increased the amount of current required to reach half-maximal pain intensity, but there were no differences in pain threshold or half-maximal pain intensity between those with or without family history of alcoholism.

Interaction Among N, Family History, and Pain.

The analgesic effect of ethanol was influenced by an interaction between N and family history. The results showed that individuals with family history of alcoholism and high N scores required significantly more electrical current to reach half-maximal pain intensity on low exposure to ethanol than those with low N scores (see Fig. 1). There were no differences in half-maximal pain intensity after exposure to placebo or high exposure to ethanol. Also, there was no difference in half-maximal pain intensity among FHNs with low and high N scores (see Fig. 2). The combination of N and family history did not alter pain threshold.

Fig. 1.

Fig. 1.

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Change in half-maximal pain intensity for individuals with low and high neuroticism scores and family history of alcoholism.

Fig. 2.

Fig. 2.

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Changes in half-maximal pain intensity for individuals with low and high neuroticisms scores and no family history of alcoholism.

Ethanol Effects

Breathalyzer Levels.

The average BrAc levels during the clamp period on the low exposure to ethanol day were mean BrAc = 0.04 g/dl with SD = 0.005 g/dl, and the average BrAc levels during the clamp period on the high exposure to ethanol day were mean BrAc = 0.1 g/dl with SD = 0.016 g/dl.

Subjective Ethanol Effects.

Subjects reported that the low exposure to alcohol was equivalent to about two drinks (mean = 1.91, SD = 1.28), while high exposure to alcohol was equivalent to about 3 drinks (mean = 3.30, SD = 1.72); there were no differences based on personality characteristics or family history. There was a significant difference between baseline and peak VAS item “buzzed” on low and high exposure to ethanol, but not on placebo (F = 28.4, p = 0.000; mean = 0.338 SD = 1.22, mean = 1.256 SD = 1.84 and mean = 2.716 SD = 2.40 for placebo, low exposure to ethanol and high exposure to ethanol, respectively). There were no differences in any subjective ethanol effects based on N scores or family history of alcoholism. There were no significant differences in anxiety, irritability, and depression during the challenge or between groups: it should be noted that these were rarely reported in this study sample during the ethanol challenge.

DISCUSSION

The results from the present study indicated that there were no differences in pain threshold or half-maximal pain intensity to an electrical stimulation in a laboratory setting in healthy volunteers based on N or family history of alcoholism. However, N and a family history of alcoholism significantly influenced the analgesic effect of an alcohol challenge, suggesting that there is a complex interaction between pain perception, N, genetic predisposition, and analgesic response.

Consistent with other research, we found that ethanol produced analgesia, and more electrical current was required on ethanol than on placebo to reach half-maximal pain intensity. The high exposure to ethanol produced a significant analgesia from pain that was not influenced by N scores or by family history of alcoholism. However, on the low exposure to ethanol, which is equivalent to approximately two standard drinks, individuals with neuroticism—who exhibit a general tendency to experience negative affect such as fear, have lower ability to control impulses and tend to cope poorly with stress (Costa and McCrae, 1992)—reported greater ethanol analgesia than those who had low N scores. Family history of alcoholism did not by itself influence ethanol analgesia but had an additive effect. The heightened analgesia in individuals with high N scores was observed among those with family history for alcoholism but not among those without family history of alcoholism. The heightened analgesia was seen in the low exposure to ethanol but not the high exposure to ethanol.

It is possible that the effect of family history or the personality trait N was not seen in the higher ethanol exposure, because at a higher ethanol exposure, the pharmacologic effects of alcohol overshadow other factors that influence pain response. There is an exposure-associated response to ethanol analgesia (Perrino et al., 2008). Our findings are consistent with other research, suggesting that the subjective effects of alcohol are more prominent at lower exposures of alcohol and are eliminated at higher exposures (O’Connor et al., 1998). Also, Stewart and colleagues (Stewart et al., 1995) reported that high exposures of ethanol (1.00 ml/kg) eliminated differences in pain response between the FHPs and FHNs. It may also be that the sedative effects during the high exposure to ethanol reduce fear and anxiety among those with high N scores (characteristics often assigned to individuals with high N) so their response to pain becomes not unlike that of individuals with low N scores. Laboratory studies using patients with social phobia, for example, lend support to this hypothesis by showing that alcohol attenuates the impact of threatening stimuli (Stevens et al., 2008). However, in this study, there were no differences in anxiety or other symptoms captured by the visual analog scales.

Our findings on the interactive effect of family history and N scores on pain and analgesia to ethanol have clinical implications in the area of alcoholism and pain research. Family history of substance use and N traits have been identified as independent risk factors for the development of alcoholism. Family history of substance use and N also affect pain response. Our results support the hypothesis that the combined phenotypes may enhance the risk for alcoholism through increased sensitivity to pain and heightened response to analgesia (Pihl et al., 1989; Schuckit et al., 2006; Stewart and Pihl, 1994). Identifying how individual phenotypes interact with one another can facilitate the development of preventative techniques and allow for more therapeutic specificity in treatment of alcoholism and pain.

Our findings differ from previous research showing that “lower tolerance” to pain is associated with high scores on N and harm avoidance among healthy subjects as well as individuals with low back pain. Also, unlike some previous studies that found that high N and HA were associated with lower threshold for pain, we found no differences in pain threshold. Other research has shown that FHPs are more sensitive to painful stimulation (Finn and Pihl, 1987; Stewart et al., 1995). We found no primary differences in half-maximal pain intensity between those with and those without family history of alcoholism. The contradictory findings on pain based on N and family history may be explained by differences in methodology. In this study, noxious electrical stimulation rather than heat, cold, or pressure pain was used. The pain paradigm in this study has a different mechanism of pain activation. Noxious electrical stimulation causes pain sensation by acting through the peripheral nervous system, while heat, cold, or pressure pain cause pain by acting on the central sensory neurons.

In this study, participants reported that BrAc = 0.04 g/dl was equivalent to approximately two standard drinks, and BrAc = 0.10 g/dl was equivalent to approximately three standard drinks. Other published studies have reported that BrAc = 0.10 g/dl is more equivalent to 5–6 standard drinks. The difference in findings may be because of the use of IV ethanol paradigm, where subjects are not exposed to the usual cues (sight, smell) associated with alcohol consumption. Lack of alcohol cues may have led to an underestimation of amount of alcohol on the high exposure to ethanol (BrAc = 0.10 g/dl) in this study.

There are some limitations to this study. Using pain paradigms that invoke stronger or different types of pain (e.g., heat, capsaicin) may yield different results. We are currently conducting experiments using capsaicin, a pain modality that is more comparable to real-life pain than electrical stimulation. Relatively small sample sizes in some cells (FHP with low N scores n = 7) may have influenced results. Analgesia was assessed to moderate levels of ethanol that are only equivalent to low doses of other analgesics such as morphine. Research examining personality characteristics as risk factors for the development of alcoholism has consistently found impulsivity, sensation seeking, and behavioral dyscontrol as best predictors of future problems with alcohol and other drug use. Although the N dimension encompasses impulsivity, using a scale that directly assesses those personality traits would better characterize subjects who are impulsive, sensation seeking, or exhibit behavioral dyscontrol.

In summary, the findings suggest that N influenced analgesia to ethanol and that family history of alcoholism had an additive effect on alcohol analgesia. Individuals with high N scores and FHP had the strongest response to ethanol analgesia but only to the low level of exposure to ethanol.

ACKNOWLEDGMENTS

Grant supported by: NIAAA Center for Translational Neuroscience of Alcoholism, NIAAA, 2P50-AA012870; VA Alcohol Research Center; Alcoholic Beverage Medical Research Foundation.

Contributor Information

Elizabeth Ralevski, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.

Albert Perrino, Department of Veterans Affairs, VA Connecticut Healthcare System, West Haven, Connecticut; Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut.

Gregory Acampora, Department of Veterans Affairs, VA Connecticut Healthcare System, West Haven, Connecticut; and Department of Psychiatry Residency Program, Boston University School of Medicine, Boston, Massachusetts..

Julia Koretski, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.

Diana Limoncelli, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.

Ismene Petrakis, Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.

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