The Role of Guilt in the Development of Post-traumatic Stress Disorder a Systematic Review

Introduction

The diagnosis of Post-Traumatic Stress Disorder (PTSD) first appeared in the 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders in 1980 (1), based largely on clinical descriptions of soldiers returning from the Vietnam state of war (2). Its definition has evolved considerably over recent decades, including its removal from the anxiety disorders in DSM 5 too as the creation of a singled-out diagnostic category for this disorder (three). PTSD is characterized by a variety of symptoms that persist over the months or years following a traumatic outcome and that notably include intrusive memories, avoidance of cues associated with the event, alterations of cognition and mood, and a land of hyperarousal. Although diverse mental disorders are frequently associated with PTSD, substance employ disorders (SUDs) are particularly prevalent (four–6). The principal hypotheses that take been formulated to explicate these associations include self-medication (implying that PTSD is the main condition and that substance use disorders occur later), the notion that addiction to substances may constitute a take chances cistron for the occurrence of traumatic events (whereby PTSD is a secondary condition), and finally the possibility that both disorders share common vulnerability factors (7). Regardless of which mechanism best explains these forms of dual disorder, the combination of PTSD and addiction leads to poorer prognosis, increases in suicide attempts, greater social disability, poorer treatment adherence, and reduced medication efficacy when compared to patients without comorbidity (viii–10). In line with these results, a recent review of clinical investigations as well documented a strong relationship between the diagnosis of PTSD and increased substance apply and relapse in dual disorder individuals (xi), but again the exact mechanisms underlying this association remain unclear.

Peckish has been studied extensively over the years and particularly over the past two decades due to acknowledgment of its crucial role in addiction (12, 13). Craving refers to the intense, urgent, and unwanted desire to swallow a substance (xiv) and it is now considered to be a core component of addiction with important diagnostic implications following its inclusion in DSM-5. Based on findings that demonstrate a prospective link between craving episodes and substance apply, peckish is increasingly viewed every bit a fundamental construct in the etiology and form of unlike forms of habit, and it is a stiff predictor of treatment outcome (15–19). Amid the diverse factors that may impact peckish, a big body of research has highlighted the major part of substance-related cues and stress (20–29). These investigations accept shown the power of substance-related cues and stress exposure to elicit craving among individuals with booze, opiate, cocaine, tobacco, and cannabis dependence. Moreover, laboratory studies have too shown that exposure to stress-related events among individuals with alcohol apply disorder (AUD) reliably elicits peckish in a manner that is as powerful equally alcohol-related cues (xxx, 31). Although like patterns of reactivity have been shown among individuals with PTSD and alcohol employ disorder afterward exposures to personalized trauma cues via "trauma scripts," such scripts were plant to provoke greater craving that not-trauma scripts and to be more salient in eliciting alcohol craving (31, 32). These results could suggest that the intrusive memories experienced by persons with PTSD and the significant stress they induce may therefore constitute major triggers of craving as well as explain reductions in treatment efficacy in this population. This pattern of findings is consistent with the findings that patients in SUD handling who study higher PTSD scores also report higher scores on craving, depression, anxiety and stress (33), with a potential relationship between PTSD severity, SUD severity and craving levels.

One hypothesis to explain the synergy of PTSD and SUDs equally a dual disorder is therefore the impact of intrusive memories or trauma-related cues on craving which, in plow, increases the risk of relapse among patients with substance use disorders. Examining this relationship across different forms of substance addiction should help elucidate the mechanisms underlying the full general increase in clinical severity in this population, and the literature on this topic is now of sufficient size to permit a reliable summary that should more fully respond to the goals of precision psychiatry and personalized medicine (34). The aim of this systematic review is to address this issue past assessing all published investigations of the bear on of PTSD and its symptoms on craving, amidst dual disorder patients.

Methods

Inquiry Design

The report involved a systematic review of the literature based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines (35).

Information Sources

This review was based on the post-obit databases: PUBMED/MEDLINE, Psychinfo, Cochrane, and Wiley Online Library. The search was performed for all years up to June, 2021.

Search

The following search terms were used:

[(≪ Addiction ≫ or ≪ Substance Employ Disorder ≫ or ≪ Substance-related Disorder ≫) and (≪ Postal service Traumatic Stress Disorder ≫ or ≪ PTSD ≫) and (≪ Craving ≫ or ≪ Urge ≫)].

Eligibility Criteria

The post-obit criteria were used to select investigations for this review:

1. Studies Published in English-Language peer-reviewed journals.

2. Studies concerning patients, with no restrictive criteria regarding age, sex, indigenous origin, or place of residence. Studies had to include participants with PTSD and SUD comorbidity, defined, or explored according to standardized questionnaires.

three. Studies including measures of craving, and assessing the impact of PTSD or PTSD symptoms on craving occurrence or severity. Information technology was non necessary that craving was designated as the primary issue of the study in order for information technology to be included in this review.

Studies were excluded if they were based on animal models, or if they were limited to briefing abstracts, dissertations, book chapters, or incomplete articles.

Report Pick

Two authors independently examined all titles and abstracts. Relevant articles were obtained in full-text and assessed for inclusion criteria separately by the two reviewers based on the inclusion and exclusion criteria previously mentioned. Disagreements were resolved via give-and-take of each commodity for which conformity to inclusion and exclusion criteria were uncertain and a consensus was reached. The reference lists of major papers were likewise manually screened in gild to ensure comprehensiveness of the review. All selected studies were read in full to ostend inclusion criteria, study type, and study population.

Quality Assessment

2 reviewers (LJ and MF) assessed the quality of data in the included studies using the Quality Assessment Tool for Observational Accomplice and Cross-Sectional Studies (S2C) from National Institutes of Health (36). This tool is comprised of fourteen questions with responses to each existence "yeah," "no," or "other" (not applicable, NA or nor reported, NR). We rated the overall quality of each included written report every bit "skillful," "fair," or "poor."

Collecting Information

Sample characteristics (including socio-demographic data, comorbidity, and treatment status), and information on written report design and methods of assessment of PTSD, SUD, and craving were extracted. Tabular array i presents these information extracted from the selected studies.

Table 1. Data items extracted from the selected studies.

Results

Study Option

A total of 247 manufactures were identified through the search of the databases. After review of titles and abstracts, 52 articles were selected for further examination. Afterwards reading the total text, 27 met inclusion criteria for this review. This process is described in the PRISMA flowchart (Effigy 1). The selected manufactures were published between 2002 and 2021.

Figure 1. PRISMA flowchart of selected abstracts and articles.

Quality Assessment

A summary of risk of bias is presented in Tabular array 2. 11 studies were considered to be of "practiced" quality, 6 were "fair" quality and 9 of "poor" quality.

Table 2. Overall quality rating of the included studies using the The National Institutes of Health quality assessment tool for observational accomplice and cross-exclusive studies.

Study Results

Report Characteristrics

Xx-seven studies fulfilled criteria for inclusion in this review, of which 12 focused on booze, 4 on tobacco, one on cannabis, 1 on cocaine, and ix on various substance use disorders (three studies on AUD and/or Cocaine Use Disorder and half dozen studies on different types of SUD). Among the 27 included studies, thirteen were experimental studies, 13 were observational studies and one was a randomized controlled trial.

In total, 3580 subjects were enrolled, of which 1960 (54.vii%) met criteria for PTSD and SUD, 1206 (33.7%) for SUD only, and 105 for PTSD only. One written report (37) did not betoken the prevalence of low vs. high PTSD scores. Participants were most often males (65.6%), with a mean age of 41.iii years. Virtually participants (due north = 3,337; 93.2%) were recruited in care facilities including outpatient (due north = 1804; 54%), inpatient (n = 497; 15%), residential (northward = 497; 15%) or either inpatient/outpatient (n = 539, xvi%) treatment programs. Among the included participants, 61.8% (n = 2212) met criteria for AUD, 10.9% (due north = 390) were current smokers, 10.7% (n = 383) met criteria for Cocaine Apply Disorder, 9.6% (due north = 343) for Cannabis Utilize Disorder, 6.vii% (due north = 241) for Opiate Use Disorder, 3.3% (due north = 118) for Stimulant Use Disorder, ii.iv% (n = 85) for Anxiolytic or Hypnotic Use Disorder, two.2% (n = 79) for comorbid Cocaine and Alcohol Use Disorder, and 1.2% (n = 45) for Polysubstance Apply Disorder.

A detailed description of all studies included and their primary results can be found in Tables 3, iv.

Table 3. Details of experimental studies included in the review.

Table 4. Details of observational and interventional studies included in the review.

Furnishings of Traumatic Cue- and Stress-Exposure on Craving Across SUD Subgroups

The xiii experimental studies selected for this review consisted, for almost part, of exposing participants with comorbid SUD and PTSD to traumatic memories, non-specific stressors, and substance-related cues, and then evaluating their responses across SUD subgroups. Seven experimental studies involved AUD, 2 involved tobacco use disorder, one involved cocaine utilise disorder, and three studies included patients suffering from AUD and Cocaine Apply Disorder.

Alcohol Utilise Disorder

The chief finding was that exposure to a traumatic memory (in the form of a script recounting a traumatic life event) generated a significantly greater increase in craving than neutral exposure and similarly to exposure to an alcohol-related cue (31, 38–forty). The studies by Coffey et al. (31) and Nosen et al.'s (38) went further, showing that the combination of exposure to a traumatic script followed by an alcohol-related cue generated greater craving than each type of exposure when considered separately. Ii studies showed that exposure to a traumatic retention increased craving more than a not-specific stressor (39, 40).

Only i report compared subjects with the comorbidity AUD and PTSD to subjects with AUD alone (41). This study establish no significant difference between the two groups in terms of peckish intensity after exposure to a not-specific stressor. Ralevski et al. (forty) institute no correlation between the intensity of peckish provoked past the different scripts (traumatic, non-specific stress, and neutral) and the severity of PTSD symptoms, measured by the Clinician Administered PTSD Scale (CAPS). Finally, Schumacher et al. (42) showed that subjects who had suffered early on childhood trauma (<13 years of age) presented a more than astringent AUD, traumatic intrusion symptoms, and post-exposure peckish (traumatic script and alcohol-related cues), than subjects who suffered their first trauma later in adolescence (xiii–18 years of age).

Tobacco Utilise Disorder

Two experimental studies addressed tobacco use disorder. Beckham et al. (43) showed that the increase in peckish, negative touch on and traumatic symptoms were stronger later on being exposed to traumatic scripts than stressful upshot scripts and neutral scripts. Subjects with PTSD experienced a more significant increase in peckish and negative affect compared to the other group. Cigarette use was associated with a reduction in craving (which was greater in magnitude after a traumatic script), every bit well as reduction in negative affect, and traumatic symptoms, independently of group type. Dedert et al. (44) found that subjects with PTSD presented more severe withdrawal symptoms and a higher peckish level for two dimensions (anticipation of reinforcing outcome, apprehension of withdrawal symptoms and negative affect release) during acute withdrawal. Participants with PTSD reported lower craving reductions subsequently smoking.

Cocaine Use Disorder

One experimental study by Tull et al. (45) assessed the result of exposure to a personalized trauma cue on cocaine craving in patients with cocaine apply disorder with or without PTSD. Subjects with PTSD had significantly higher craving for cocaine than other participants later the traumatic script.

Multiple Type of Substance Utilize Disorder: Alcohol and/or Cocaine Use Disorder

3 experimental studies exposed subjects with alcohol and/or cocaine addiction and a history of traumatic events to combinations of traumatic or neutral scripts and substance-related or neutral cues (32, 46, 47). All studies showed that exposure to traumatic memories and substance-related cues increased craving and negative impact significantly more than neutral exposures. The studies of Saladin et al. (47) and McHugh et al. (46) showed a positive correlation between the severity of PTSD symptoms and the intensity of craving subsequently traumatic exposure. Finally, McHugh et al. (46) observed a positive correlation between the level of anxiety sensitivity (tendency to react with fearfulness to signs and symptoms of anxiety) and the severity of traumatic symptoms and negative touch on, only not peckish after the exposures.

Association Between PTSD Symptoms and Craving Across SUD Subgroups

A total of fourteen studies investigated the association between PTSD symptoms and craving beyond SUD subgroups: 12 were observational studies (five for AUD, two for Tobacco Use Disorder, one for Cannabis Utilise Disorder, and 4 for dissimilar types of Substance Utilize Disorders), 1 was an experimental study and ane was a Randomized Controlled Trial among AUD individuals.

Alcohol Utilise Disorder

V cross-sectional observational studies examined correlations between different variables related to PTSD and AUD. The studies past Lyons et al. (48) and Heinz et al. (49) constitute a correlation betwixt the intensity of peckish for alcohol on the one paw and the severity of PTSD symptoms and consumption on the other, in comorbid subjects. For Lyons et al. (48), traumatic cognitions (self-deprecation, dangerousness of the world) generated negative affect, which in plow triggered craving. Jayawickreme et al. (50) also found a positive correlation between traumatic cognitions about oneself (self-depreciation and tendency to blame oneself), negative beliefs most the globe and the intensity of craving, but this relationship was only meaning in men. Finally, Drapkin et al. (51) compared the psychosocial functioning of subjects with comorbid PSTD and AUD with those with SUD or PTSD lonely. The authors found that social functioning was more impaired (less education, lower income, more unemployment), equally well equally more severe depressive symptoms and cravings, in the comorbid subjects.

In a 28-twenty-four hours study using a daily monitoring with an Interactive Voice Response (IVR), Simpson et al. (52) plant that PTSD severity was positively correlated with craving level on the same twenty-four hour period but not the following day. In a more specific way, some traumatic symptoms (startle, irritability), were positively correlated with peckish levels on the same day, whereas other symptoms (nightmares, emotional edgeless, hypervigilance), predicted craving increases on the post-obit day. On the other hand, peckish intensity on a given day was non correlated with PTSD symptom severity on the post-obit day.

2 studies assessed the impact of changes of PTSD symptoms overtime on craving after specific treatment approaches. In a randomized clinical trial conducted by Kaczkurkin et al. (53), 165 comorbid subjects were randomly assigned to four different handling groups: Naltrexone + exposure therapy, Naltrexone lone, exposure therapy + placebo, and placebo alone. At baseline, participants with greater levels of PTSD symptom severity endorsed a significantly greater percentage of days drinking and booze craving. The percentage of days drinking was positively correlated with alcohol craving. Participants in the Naltrexone + exposure therapy group had a greater decrease in craving than in the Naltrexone lonely group. Subjects with higher initial PTSD severity had a more rapid decrease in peckish intensity over time. Finally, the percentage of drinking days and the severity of traumatic symptoms at time t predicted the intensity of craving at time t + 1, with booze peckish beingness dependent on the corporeality of PTSD symptoms and alcohol apply reported at the previous fourth dimension point. Coffey et al. (30) compared the effectiveness of exposure therapy and relaxation-based therapy in 43 subjects with comorbid AUD and PTSD using a laboratory-based experiment. A commencement session conducted before the beginning of treatment showed an increase in peckish and emotional distress of the participants after exposure to a traumatic script and alcohol-related cues. Follow-upward analyses after half dozen sessions of group exposure therapy plant a reduction of both PTSD symptoms and alcohol craving overtime.

Tobacco Use Disorder

In 2014, Dedert et al. (54) used Ecological Momentary Cess (EMA) to follow smokers with PTSD in daily life over 14 days. Participants were allowed to smoke freely during the first week, then had to begin withdrawal without any substitute or pharmacological handling in the 2d week. Compared with the pre-withdrawal phase, abstinence was associated with reductions in PTSD symptoms and craving, but not negative impact. During withdrawal period, an increase in traumatic symptom intensity predicted an increase in craving at next EMA evaluation, but the opposite association was not observed.

Rosenblum et al. (55) compared 3 groups composed by 162 Us Army veteran daily smokers: a PTSD group (52 subjects with PTSD solitary or with a comorbid depressive episode); a depressive episode group (52 subjects with depressive episode without comorbidity); and a control group (58 subjects with no psychiatric disorder). The PTSD group (with or without depression) described higher craving than the command group without whatever psychiatric disorder.

Cannabis Use Disorder

Boden et al. (56) explored the links betwixt PTSD and different characteristics associated with cannabis use (motivation, relational problems, withdrawal symptoms, and peckish) in veterans with cannabis use disorder with and without PTSD. Patients with PTSD used cannabis more often equally a coping strategy and reported a significatively higher level of craving in several components (compulsive, anticipating release of emotional distress, and use planification). Traumatic symptom severity was positively correlated with the emotional component of craving (release of emotional distress).

Multiple Blazon of Substance Apply Disorder

Two studies assessed the course of craving during SUD treatment according to PTSD symptoms severity at baseline. Wieferink et al. (33) assessed outcomes of standard, non-integrated SUD treatment amidst 297 SUD outpatients (AUD, or Cannabis or Cocaine Utilize Disorder) with higher (≥48) or lower (<48) PTSD symptom severity based on the Cocky-Reported Inventory for PTSD (SRIP). At baseline, there was no difference in the number of days of use between subjects, however, subjects with more severe PTSD symptoms had significantly college levels of craving and anxiety-depressive symptoms. After 3 and 6 months of treatment, there was a decrease in the number of days of utilise for all subjects, a significantly greater decrease in craving for subjects with more astringent traumatic symptoms, and a significant decrease in anxiety-depressive symptoms for subjects with severe traumatic symptoms only. However, patients with college levels of PTSD symptoms still reported significantly higher scores on depression, anxiety and stress after vi months of SUD treatment. Peck et al. (57) assessed the touch of a half dozen weeks therapeutical program including cognitive processing therapy, Alcoholics Anonymous (AA) meetings, and group give-and-take with 72 American veterans suffering from PTSD and a substance use disorder (AUD, Cannabis Use Disorder, Cocaine Use Disorder, Opiate Employ Disorder, Amphetamine Use Disorder, or Anxiolytic Use Disorder). Baseline dysfunctional cognitions associated with the trauma were positively correlated with PTSD and craving severity. Notwithstanding, PTSD severity was not correlated with craving levels. Cognitive processing therapy was associated with significant improvements in erroneous cognitions, trauma-cued substance craving, and depressive or trauma-related symptoms. Reduction in depressive or trauma-related symptoms was partly explained by the therapy'southward touch on on erroneous cognitions, reverse to craving.

In a cantankerous-sectional report, Driessen et al. (58) focused on the relationship between the type of addiction (alcohol or drug addiction or both), the severity of the addiction and of craving, and the presence or not of comorbid PTSD. Participants with PTSD had a higher addiction severity score, were more ofttimes hospitalized, had a shorter forbearance time between relapses and experienced craving more often than other participants. Somohano et al. (37) assessed the correlation between severity of dissimilar symptoms of PTSD and craving according to iv classes of substances: alcohol, psycho-stimulants (cocaine, amphetamines), opiates and cannabis. Concerning subjects with alcohol utilize disorder (n = 131), global PTSD severity and hypervigilance levels were associated with peckish intensity. For participants with psychostimulant use disorder (n = 66), peckish levels were correlated with global PTSD severity and more precisely with avoidance syndrome intensity. Among subjects with opiate use disorder (n = 36), global PTSD severity was correlated with craving levels, only with no association to specific symptoms. Finally, for subjects with cannabis employ disorder, no variable was associated with craving. An observational study led by Vogel et al. (59), highlighted a positive correlation between craving levels and PTSD symptoms over half dozen days following admission for detoxification among comorbid patients (PTSD with alcohol, cannabis, sedatives or mixed use disorder). Still, no correlation was found concerning PTSD symptoms at Twenty-four hour period 1 and peckish the following day.

Association of Negative Affect With Trauma Exposure and Craving

Alcohol Use Disorder

Several studies focused on the function played by negative bear upon during different forms of exposures (31, 38, xl). The results were similar to those obtained for craving and showed that exposure to a traumatic script and an booze-related cue generated a more than intense level of negative affect than during a neutral exposure. Nosen et al. (38) reported that in a traumatic context (exposure to a traumatic script), the intensity of craving was correlated with the severity of negative affect. The study of Coffey et al. (30), through a laboratory-based experiment, found a decrease of both peckish and emotional distress after trauma-focused imaginal exposure, suggesting that negative emotions should plant a mechanism of alcohol craving induced by trauma exposure. Lyons et al. (48) examined more specifically the mediation role of negative affect on the clan between PTSD cognitions and craving amongst 136 handling-seeking veterans with PTSD and AUD. Mediation models demonstrated that negative affect mediated the association between specific posttraumatic cognitions related to the cocky, the earth, the self-blame, and craving controlling for PTSD/AUD symptom severity and gender. Posttraumatic cognitions were associated with increased negative bear on, which in turn was related to increased craving. Finally, one observational study (50) examined sex differences in trauma cognitions and their relationship to symptoms of AUD including craving. Specifically, negative cognitions virtually the cocky were associated with increased craving in men, just non in women, a finding that could be related to greater subjective negative emotions related to traumatic experiences in men. In this perspective, higher craving levels could be explained as a result of maladaptive coping of trauma-related negative emotions.

Tobacco Use Disorder

The study of Dedert et al. (54) investigated whether craving for cigarettes was driven by PTSD symptoms and negative affect amid smokers with PTSD attending to quit, using an EMA procedure. Negative emotions were identified as predictors of craving during the withdrawal period (54). Increased PTSD symptoms and negative affect predicted an increase in peckish at the next EMA evaluation, fifty-fifty on days with low levels of craving, but the opposite association was not observed.

Cocaine Apply Disorder

In the experimental study of Tull et al. (45), in male subjects only, the experience of negative emotions (shame, guilt) in response to the traumatic script mediated the relationship between traumatic symptoms and craving for cocaine. The experience of self-witting negative touch on in response to the trauma script accounted for the relation between PTSD diagnosis and cocaine craving following trauma script exposure.

Discussion

20-seven studies fulfilled criteria for inclusion in this review, of which 12 focused on booze, 4 on tobacco, 1 on cannabis, 1 on cocaine and ix on various substance apply disorders. The results showed that regardless of substance type, PTSD and SUD dual disorder was associated with more intense craving levels and was characterized past a prospective link between PTSD symptom severity and craving episodes. Exposure to traumatic memories in experimental studies was associated with emotional distress whose severity was correlated with craving intensity (31, 38).

Whatever for alcohol (31, 38), tobacco (43), or cocaine (47), experimental results showed that exposure to traumatic cues amidst subjects with PTSD and substance use disorder comorbidity triggered peckish in the same way every bit exposition to substance cues. There also was an condiment effect of the association of both forms of exposure on craving, a finding that is consistent with literature showing an clan between exposure to stress and craving among patients with substance use disorder (26, 60). However, beyond stress exposure, there appears to be a specific effect of traumatic memories on peckish. According to the study by Beckham et al. (43), exposition to traumatic cues triggered significatively greater craving compared with exposure to not-traumatic stress cues. This result could explain the lack of difference in peckish levels between subjects with and without PTSD, after exposition to a common cold pressor task (neutral stress) in the investigation past Brady et al. (41). In this way, persons with these comorbidities are repeatedly exposed to traumatic memories and therefore to more than intense peckish, which could increase the hazard of relapse. Moreover, the written report past Boden et al. (56) lends back up to this estimation by highlighting the correlation between traumatic symptom severity and craving intensity. Finally, studies using EMA observed a prospective link in the association between PTSD symptoms and craving, showing notably that craving daily variation was a reaction to traumatic symptoms intensity. Such results are generally supportive of self-medication theory, as bedevilment of PTSD symptoms would and so trigger greater craving and atomic number 82 to substance use as a means of assuaging traumatic symptoms.

In line with this estimation, some studies in this review also highlighted the role of negative affect associated with traumatic exposure in the chance of relapse and thereby indicating that substance use may plant a coping strategy to bargain with negative touch. Experimental studies amid subjects with booze and tobacco use disorder (31, 38, 43) showed a correlation in evolution of negative impact and peckish later exposition to a traumatic gene. Moreover, negative emotions were identified every bit predictors of craving after exposition to traumatic cues likewise equally in daily follow-ups during withdrawal (54). This literature has also demonstrated a salient clan betwixt PTSD, addiction and negative emotions, and points specifically to the mediation role of negative emotions and the human relationship between traumatic symptoms and alcohol utilise (61). According to Zvolensky et al. (62), smokers experience greater negative affect if they have comorbid PTSD. Individuals with comorbidity would likewise use emotions to assuage emotional distress, in accordance with the principle of negative reinforcement. This dysphoric state could be explained by a decrease in dopaminergic D2 receptor density in the reward network (ventral striatum) amongst persons with substance utilise disorders (63) and a college number of DAT dopamine transporters in persons with PTSD (64) that are correlated with peckish intensity. Perturbations of the stress axis could also exist implicated in these dual disorders, every bit anomalies of the stress response amongst subjects with substance use disorders is associated with the activation of actress hypothalamic corticotropin-releasing cistron (CRF) synthesis, excessively activating the amygdala (the brain construction implicated in emotional reactions such as fear) (65, 66). Such hyperactivity has also been observed among individuals with PTSD (67) and information technology is associated with the presence of enduring negative emotional states (feet, irritability, dysthymia). While the prefrontal cortex has a major impact on emotional regulation by the inhibition of the amygdala (68), SUD and PTSD are both associated with a hypoactivation of this expanse (69, 70) that could explicate the major emotional dysregulation amidst these cases of dual disorder (71, 72). Thus, a negative emotional country or emotional dysregulation characterized by significant fluctuations in daily life could constitute a clinical feature of these dual disorders leading to greater craving frequency and/or intensity, although this hypothesis requires further investigation.

Another important ascertainment of this review that could further agreement for mechanisms underlying PTSD and craving is the impact of early trauma. Schumacher and colleagues (42) demonstrated that patients with dual disorders and early trauma (<xiii y.o.) experienced more astringent PTSD symptoms, more than craving after exposure, and more astringent AUD. This is consistent with previous studies highlighting a link between historic period that the trauma was experienced and PTSD severity (73). The link with craving intensity could be partly explained by the fact that early trauma leads to deficit in inhibitory control during stress exposure, which might facilitate the employ of substances as coping strategy (74). Indeed, deficits in inhibition capacities during adolescence is known to be associated with a greater risk of both substance experimentation and the development of substance employ disorders (75).

Several limitations of this systematic review should exist considered in interpreting its findings. A first concern is the heterogenous nature of the selected studies. Based on the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies (S2C), well-nigh studies included in this review could be qualified equally being of "Good" or "Fair" quality (northward = 17 or 65%). However, nine studies (35%) were classified equally "Poor" quality, and this may partly explain the considerable variation observed in report methods. The bulk of investigations classified as "Poor" quality were observational studies while virtually of the "Good" quality studies were cantankerous-sectional in nature. Moreover, the studies used a big variety of questionnaires to assess SUD, PTSD, and craving. Substance apply was mainly reported using cocky-report questionnaires and only six studies used objective methods of cess (urine or breath tests). Nevertheless, the majority of experimental studies on cue-reactivity administered single-particular instruments, mainly visual analog scale which are considered every bit an acceptable and valid tool in experimental paradigms, while observational studies used unlike multi-items questionnaires. The heterogeneity of cocky-report measures of craving and research pattern in observational studies could explain some variability in the findings. Finally, few studies addressed sex differences in the analysis, although some results indicated specific relationships between trauma-related cognitions and emotions (cocky-depreciation and cocky-blame) and craving among males. More comprehensive analyses are needed to examine the bear upon of sexual practice (and gender) on the underlying relationship between PTSD and SUD across different SUD subgroups. Despite these limitations, the results strongly underscore the strong relationship between PTSD and substance craving and the necessity to concomitantly care for SUD and PTSD as dual disorder.

Concerning handling approaches, recent studies assessed several classes of pharmacological agents in the treatment of this dual disorder based on neurobiological mechanisms implicated in both disorders when considered individually (76). Moreover, the positive consequence on alcohol use and traumatic symptoms was demonstrated with the association of Disulfiram and Naltrexone in a randomized trial (77), and the apply of Desipramine led to an improvement of booze use and PTSD symptoms (78). Promising results have also been found with treatments using noradrenergic (Prazosine, Propranolol), GABA and glutamatergic system (Memantine, North-Acetyl-Cysteine, and Topiramate). The results of this review also suggest the importance of improving regulation of negative emotions associated with traumatic memories, and treatments of erroneous or dysfunctional cognitions linked with the traumatism. Furthermore, the potential mediation role of post-traumatic cognitions on negative impact and craving raises the effect to consider posttraumatic cognitions and negative emotions as a salient target for craving reduction. On this issue, several therapies targeting emotion regulation and dysfunctional cognitions linked with traumatism such as Prolonged Exposure and Cognitive Processing Therapy were found to be efficacious for substance utilise, craving and PTSD symptoms (53, 57, 79). The study of Coffey et al. (30) using trauma-focused exposure therapy led to reductions in negative affect and craving, although the potential link between negative post-traumatic cognitions, negative affect and craving was non specifically assessed. Integrated treatment combining prolonged exposure and naltrexone among individuals with comorbid PTSD and AUD demonstrated better outcomes in terms of alcohol craving compared to exposure lonely or naltrexone solitary. The necessity of global handling approaches for comorbid patients, including pharmacological treatment, psychotherapies, and psycho-social handling has also emphasized (eighty), but farther studies are needed in other SUD populations to generalize these findings and examine the temporal changes of emotion dysregulation, trauma-related emotions such as guilt and shame, on subsequent craving and substance use.

Conclusions

Findings from the electric current study further inform our understanding of the synergetic relationship between PTSD and SUDs that lead to craving that is greater than that observed with either disorder alone. PTSD symptoms can human action as powerful craving cues with an additive effect when combined with exposure to substance-related cues, thereby constituting a salient gamble factor for relapse. The craving elicited past PTSD may differ according to specific PTSD symptoms and the furnishings of specific forms of substance apply, although this possibility requires further investigation. Daily life studies using Ecological Momentary Assessment appear to be particularly adapted to investigating the temporal relationship between different PTSD symptoms, emotional states and the clinical expression of addiction, and hold considerable promise for the development of more personalized interventions in dually-diagnosed individuals. Since the bulk of the studies included in our review concern alcohol and tobacco, it would be besides interesting to expand this research to other substances as well as to behavioral addictions. Specifically, no studies examined the association between craving and MDMA or psychedelic drugs, that is a major issue in view of novel treatment approaches of PTSD.

Our information therefore challenge our current clinical practise in the treatment of patients suffering from dual diagnosis, and argue for the integration of an additional trauma-focused strategies into addiction facilities, notably including cognitive-behavioral therapies based on prolonged exposure. While all individuals suffering from SUD should be systematically assessed for trauma history and PTSD, the present data suggest that PTSD treatment should not exist delayed until abstinence has been achieved. The straight relationship between PTSD symptoms and craving argues for the demand of these integrated therapies in the goal of providing the about comprehensive and efficacious treatment possible.

Data Availability Statement

The original contributions presented in the written report are included in the article/supplementary cloth, further inquiries can exist directed to the corresponding author/due south.

Author Contributions

FR, LJ, JS, and MF designed the review, wrote, and reviewed the manuscript. FR and LJ reviewed the abstracts and the papers. FR, LJ, and MF obtained the data from the selected articles. All authors approved the final version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or fiscal relationships that could be construed as a potential conflict of interest.

Publisher'due south Note

All claims expressed in this article are solely those of the authors and do non necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may exist evaluated in this commodity, or claim that may be made by its manufacturer, is not guaranteed or endorsed past the publisher.

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