Pain in veterans of the Gulf War of 1991: a systematic review

Background Veterans of the Persian Gulf War of 1991 have reported a range of adverse health symptoms. This systematic review aims to identify all studies that have compared the prevalence of symptoms of pain in veterans of the Gulf War to that in a non-Gulf military comparison group, and to determine whether Gulf War veterans are at increased risk of reporting pain. Methods Studies published between January 1990 and May 2004 were identified by searching a large number of electronic databases. Reference lists and websites were also searched and key researchers were contacted. Studies were included if they reported the prevalence of any symptom or condition that included the word "pain" in Gulf War veterans and in a comparison group of non-Gulf veterans. 2401 abstracts were independently reviewed by two authors. Results Twenty studies fulfilled the inclusion criteria. Five main sites of pain were identified (muscle, joint, chest/heart, back and abdominal pain) and separate meta-analyses were performed to summarise the results related to each site. A greater proportion of Gulf veterans reported symptoms at each site of pain when compared to a non-Gulf military group. Gulf deployment was most strongly associated with abdominal pain, with Gulf veterans being more than three times more likely to report such pain than a comparison group (OR 3.23; 95%CI 2.31–4.51). Statistical heterogeneity between study estimates was significant, probably due to variation in measured periods of prevalence and symptom measurement methods. Conclusion A higher proportion of veterans of the Persian Gulf War of 1991 reported symptoms of pain than military comparison groups. This is consistent with previously demonstrated increased reporting of more general symptoms (fatigue, multiple chemical sensitivity, post traumatic stress disorder) in these veterans compared with non-Gulf military groups. However, the primary studies were heterogeneous and varied greatly in quality.


Background
Shortly after returning from the Gulf War in 1991, veterans started to report a range of adverse health symptoms [1]. One of these reported symptoms was pain, primarily of musculo-skeletal origin [2]. Indeed, experience of musculo-skeletal symptoms (including symptoms of pain) became a necessary element in the definition of Fukuda's chronic multisymptom condition used to label the poor health described by veterans of the Gulf War [3]. Pain can therefore be seen as an important factor in military health.
However, pain is not uncommon in either the general population or in non-deployed military cohorts [4]. Pain in military cohorts is primarily associated with injuries arising from increased levels of physical activity experienced in military training [5]. Any investigation into the relationship between deployment to the Gulf War and subsequent experience of pain must account for this. The investigations are also made more difficult through the reliance on a self-reported measurement of health outcome. Studies that have attempted to clinically confirm self-reported pain have shown little association between the self-reported and clinical measurements, possibly due to the sometimes transitory nature of pain [6].
This paper describes a systematic review of studies comparing the prevalence of symptoms of pain in veterans of the Gulf War with its prevalence in a comparison group who were not deployed to the Gulf (non-Gulf veterans).

Searching
The methods employed in the systematic review have been described in another paper [7] and are summarised here. 5387 studies from the period January 1990 to May 2001 were identified for possible inclusion by searching through databases (EMBASE, Medline, ASSIA, SIGLE, Psy-cINFO, CancerLit, HealthSTAR, Dissertation Abstracts, Current Contents, Health and Psychosocial Instruments, CINAHL and Biological Abstracts) and websites and by contacting researchers in the field. Studies were eligible for inclusion if they contained data on military, medical or peace-keeping personnel who were deployed to the Gulf War together with a comparison group which differed in its level of exposure. Abstracts of 2296 references that remained eligible were examined by two members of the research team. Studies were excluded if they measured simulated exposures, if they measured non-health related outcomes or if the subjects were inhabitants of the Persian Gulf rather than deployed military personnel. Studies that examined pain within groups of Gulf veterans that had experienced differential exposures whilst in the Gulf, e.g. exposure to the smoke from oil-well fires, were also excluded from this review.
All included studies were categorised by health outcome, one of which was pain. Any site of the body where pain was reported was included within the review. The definition of pain in this review therefore included any symptom or condition that included the word 'pain', e.g. 'chest pain', 'joint pain' and 'muscle pain'. It did not include any symptom or condition that is frequently associated with pain, such as arthritis, fibromyalgia or headache. Thirteen papers were identified from this search.
An updated electronic search of the literature from January 2001 to May 2004 was completed which identified a further 538 references. Of databases searched in 2001, CancerLit and HealthStar were now incorporated into Medline whilst Dissertation Abstracts and Health and Psychosocial Instruments were no longer available. Two databases not searched in 2001, the Web of Knowledge Databases and the Science and Social Science Citation Indexes were included in this updated search. Of 538 potentially relevant references, 105 were selected from the abstract (or title if no abstract) as potential research studies with a relevant comparison group. From these, seven papers were identified and therefore this review contains 20 papers that fulfilled our inclusion criteria and which contained data relating to pain both in Gulf War veterans and non-Gulf veterans. These non-Gulf veterans may or may not have been deployed elsewhere on active duty.

Data extraction
Data relating to the studies' main hypotheses and to methodological quality were extracted independently by two members of the research team onto pre-designed data extraction forms. Information on methodological quality of the individual studies included the response or followup rate, the potential of selection bias in the sampling of subjects, the potential bias in the measurement of outcomes, and the availability of data on confounders and the controlling for such variables.

Statistical analysis
Meta-analysis statistically combines and analyses data from separate studies with the aim of appraising the evidence objectively, providing a more precise estimate of effect and exploring any heterogeneity between the results of individual studies [8]. A summary odds ratio was calculated with a random effects model using the DerSimonian and Laird method [9]. The estimate of heterogeneity between studies was taken from the inverse variance fixed effect model. All analyses were performed using the "metan" command [10] in Stata Version 9 (Stata Corporation, College Station, TX, USA). We chose to use this approach because of our a priori view that the studies were inherently heterogeneous.

Studies identified
The twenty studies that fulfilled the inclusion criteria are described in Table 1 [3,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. Three further studies were also identified but excluded on the grounds that their inclusion would have lead to duplication of data within the results [30][31][32]. Gray et al [30] presented data relating Estimates were weighted to control for stratification variables: gender and unit component  to the same study population described by Knoke et al [24] but included fewer pain outcomes, therefore data reported by Knoke et al are utilised. Wolfe et al [31] reported overall bodily symptom scores (not specifically pain), therefore data relating to pain outcomes quoted in Proctor et al [18] have been included instead. Finally, since Nisenbaum et al [32] presented data on the same study population as Fukuda et al [3] only data from Fukuda et al are included.

Muscle pain
Prevalence of 'muscle pain' was measured in eight of the studies ( Table 2). Veterans were asked to report whether they had "muscle pain" [3,20,23,25,29], "unusual muscle pain" [24,27] or "muscle pain/weakness" [28]. Ishoy et al [20] presented no clear numerical data on muscle pain and therefore the results could not be included in the meta-analysis, but instead stated that there were no statistically significant differences in the reporting of pain between the Gulf veterans and non-Gulf veterans. The overall reported prevalence of muscle pain was highest amongst the Gulf War veteran study sample of Kelsall et al [29], but the non-Gulf veterans also reported a particularly high prevalence which therefore resulted in a weak association between deployment and symptoms. Conversely, the prevalence of muscle pain reported both by Gulf and non-Gulf veterans was unusually low in the study sample of Simmons et al [28]. These authors were the first to measure health outcomes using an open-ended question enquiring about any new medical problems or changes in general health since 1990 instead of relying on respondents to tick relevant boxes for pre-defined categories of symptoms. This method of data collection might minimise over-reporting of symptoms.
The meta-analysis provided a summary estimate of OR 3.06 (95% CI 2.18-4.30) reflecting an independent association between deployment to the Gulf War and subsequent reporting of muscle pain. Significant statistical heterogeneity (χ 2 = 173.1 df = 6 P < 0.001) was found between the studies. Table 3 lists the twelve studies that included joint pain as a reported outcome. Ishoy et al [20] presented no clear numerical data but again stated that there were no significant differences in the reporting of joint pain between Gulf and non-Gulf veterans. Most of the studies reported that approximately 30-40% of Gulf veterans experienced symptoms of joint pain, making it one of the most common sites of pain. A particularly large proportion (74%) of Gulf War veterans reported joint pain in the study sample of Sostek et al [12]. The authors themselves suggested that a reporting bias might be present in the study as a greater proportion of Gulf War veterans also reported a change of colour of their fingernails which was included as a control symptom.

Joint pain
Overall the odds of reporting joint pain was nearly three times greater amongst the Gulf veterans as summarised by the meta-analysis (OR 2.81; 95%CI 2.31 -3.42). There was significant statistical heterogeneity between the study results (χ 2 = 144.7 df = 10 P < 0.001).

Chest or heart pain
Chest or heart pain was reported in seven of the studies (Table 4). Data from Cherry et al [26] could not be included in the meta-analysis since they were presented as mean scores rather than prevalence estimates. Data from Proctor et al [18] were not included in the meta-analysis because the prevalence of symptoms in the non-Gulf veterans was zero and did not allow for a meaningful comparison. An unusually low prevalence of symptoms was again observed in the study sample of Simmons et al [28], although the ratio measure arising from the data was consistent with those across the studies. The meta-analysis provided an overall summary estimate of OR 2.52 (95%CI 2.23-2.85). The test for heterogeneity was not significant (χ 2 = 7.4 df = 4 p= 0.115) which suggests that the estimates from individual studies were consistent with each other. Table 5 shows the prevalence estimates reported by six studies investigating back pain as an outcome. It was not possible to include data from the Goss Gilroy study [17] in the meta-analysis since no indication of exact sample size was provided. The overall summary estimate was OR 1.58 (95%CI 1.23-2.04). Again, there was significant statistical heterogeneity between the study results (χ 2 = 49.8 df = 3 P < 0.001). Table 6 summarises the results of six studies that investigated the association between Gulf deployment and abdominal pain. The mean symptom scores reported by Cherry et al [26] could not be included in the meta-analysis. The reported prevalence of this symptom in Gulf War veterans varied greatly between studies, ranging from three percent to seventy percent. This particularly high prevalence reported by Sostek et al [12] will certainly have contributed to the statistical heterogeneity between study

GWV -Gulf War veterans; NGV -non-Gulf veterans.
OR -odds ratio. Individual study ORs based on published prevalence data and not adjusted for confounders. Summary OR -weighted average of all individual study ORs, derived from "metan" command in Stata version 9.0 using a random effect model and DerSimonian and Laird method. estimates, even though the study carried least weight in the meta-analysis. The overall summary estimate generated by the meta-analysis (OR 3.23; 95%CI 2.31-4.51) was therefore not surprisingly associated with significant statistical heterogeneity between the studies (χ 2 = 29.8 df = 4 P < 0.001). GWV -Gulf War veterans; NGV -non-Gulf veterans. OR -odds ratio. Individual study ORs based on published prevalence data and not adjusted for confounders. Summary OR -weighted average of all individual study ORs, derived from "metan" command in Stata version 9.0 using a random effect model and DerSimonian and Laird method.

Other sites of pain
Four studies reported the prevalence of symptoms of either body pain, widespread pain or general aches whilst three studies measured scores of bodily pain using the SF-36 [11,13,15,16,19,25,26]. A meta-analysis was considered inappropriate to summarise the results due to the variation in measurement of the symptom. All seven studies reported a positive association between Gulf deployment and painful symptoms, however those symptoms were measured. For example, 19.2% of Gulf veterans versus 9.6% of non-Gulf veterans reported chronic widespread pain in the sample of Peloso et al [16]. Similarly 12.2% of Gulf veterans versus 6.5% of non-Gulf veterans reported widespread pain in the sample of Cherry et al [26].

Discussion
Nineteen of the twenty primary studies identified by this review recorded that a greater proportion of veterans of the Persian Gulf War of 1991 reported painful symptoms compared to other military service personnel who were not deployed to the Gulf War. For all five sites of bodily pain, each of the summary estimates from the meta-analyses indicated deployment to the Gulf War was associated with increased odds of reporting painful symptoms. Gulf deployment was most strongly associated with abdominal pain, with Gulf veterans being more than three times more likely to report such pain.
Unfortunately the majority of studies included in this review did not investigate whether Gulf War veterans report more symptoms of severe pain than non-Gulf veterans. Only Kang et al and Kelsall et al reported prevalence estimates separately for moderate to severe symptoms.
Kang et al found that a greater proportion of the Gulf veterans than non-Gulf veterans reported more severe symptoms of joint pain, but they did not differ from non-Gulf veterans in the severity of symptoms of back, muscle or abdominal pain [23]. Kelsall et al reported that more of the Gulf veterans suffered from general muscle aches and pains that were more severe in nature but that their degree of symptoms of back or joint pain was the same as non-Gulf veterans [29].
Statistical heterogeneity between study estimates for a particular site of pain was significant (with the exception of chest pain). Variation in each of the following characteristics across studies probably contributed to this heterogeneity: sampling strategy (single military units versus stratified random samples), degree of differential response rates between Gulf and non-Gulf veterans, method of symptom ascertainment, measured period of prevalence and specific definition of symptoms.
At least the statistical heterogeneity that arose probably reflects heterogeneity in the strength of association rather than the direction of association.
The prevalence of painful symptoms amongst Gulf War veterans was most often reported to be between approximately 20% and 40% depending on the site of pain and exact definition of measurement. In contrast, a recent population-based survey of young adults aged 18 to 25 years in the UK observed that 66.9% (95%CI 63.7% to 70.1%) reported any pain within the previous six months, although a low response rate (37%) means the estimates should be interpreted with caution [33]. The prevalence of pain amongst military personnel when compared to the general population might be expected to be relatively low due to a "healthy worker" effect, but conversely the increased risk of pain received through injuries during military training may contribute to the prevalence of pain in military populations. This highlights the need in study samples for a relevant comparison between veterans deployed to the Gulf War and either veterans deployed elsewhere or non-deployed military personnel.

Limitations of primary research
Sampling of participants In a cross-sectional survey it is important to derive a random sample of all those subjects who are potentially eligible in order to generate a representative sample of the larger population of interest. Those studies which selected a random sample of veterans from either US, British, Canadian, Danish or Australian military personnel databases are likely to have fulfilled this criterion [17,20,21,23,26,28,29]. However, those studies which sampled more opportunistically from individual military units are more prone to selection bias [3,11,12,18].

Response bias
In general, most of the studies achieved a satisfactory response rate amongst veterans of the Gulf War. However the response rate amongst non-Gulf veterans unfortunately tended to be systematically lower in most studies for which data were available. Differences in response rates between the exposed and unexposed groups can lead to bias if the responders are systematically different to non-responders. Unwin et al [21] intensively followed up a random selection of non-responders and found that those with more symptoms responded earlier but there was no significant interaction between deployment, late response and health outcome. So the prevalence estimate of symptoms might be a biased overestimate, but relative measures of effect as reported in this review should be less prone to bias. Kelsall et al [29] also suggested that response bias is unlikely to fully explain any differences observed between Gulf and non-Gulf veterans. They reported that odds ratios from a prediction model which assumed full participation and accounted for age, rank and service were only marginally lower than corresponding odds ratios observed for participants.

Symptom measurement
All of the studies relied on the veterans' self reported symptoms of pain which would be prone both to random measurement error and more importantly to measurement bias. Two studies included symptom items in their questionnaires which were not thought to have any physiological basis but were designed to estimate the level of over-reporting of symptoms amongst Gulf War veterans. For example Knoke et al [24] found that 1.2% of Gulf veterans versus 0.2% of non-Gulf veterans reported symp-toms of 'earlobe pain', whilst Sostek et al [12] reported a significantly greater proportion of Gulf veterans reported a 'change in the colour of fingernails'. These results suggest that at least some of the association between Gulf deployment and reporting of painful symptoms might be explained by systematic over-reporting of symptoms amongst Gulf veterans.
In an attempt to minimise the measurement error and possible bias that might be associated with the reliance on symptom checklists, Simmons et al [28] introduced the use of open-ended questions enquiring about any new medical problems or changes in general health since 1990. This method of data collection was indeed associated with lower overall prevalence of symptoms but still demonstrated greater reporting of symptoms amongst Gulf War veterans relative to non-Gulf veterans.

Confounding
A few of the earliest studies did not attempt to control for potential confounders in any way and therefore may have inflated estimates of risk [3,11,12]. Some studies accounted for the effect of gender by restricting their analysis to a single sex [21,22,24,28,29], whilst some studies made adjustments for a number of confounding variables in the analysis of the data [18,19,21,22,25,[27][28][29]. However, the later and larger studies tended to control for potential confounders more thoroughly in the sampling design of the study by matching veterans on age, sex and at least some aspect of military status [13][14][15][16][17][20][21][22]26,28,29].
Since the meta-analyses are based on the raw prevalence data from each study, potential confounders could only be partially accounted for in the resulting summary odds ratios if individual studies stratified both the Gulf and non-Gulf samples on age, sex or military status. To estimate the size of the possible effect of confounding on our reported summary estimates, it would be useful to compare the unadjusted and adjusted results from any of the primary studies. However very few of the primary studies report both raw and adjusted results. Unwin et al reported an unadjusted OR of 2.8 (95%CI 2.5-3.2) for joint pain in male Gulf veterans versus era controls which was reduced to an OR of 2.2 (95%CI 2.0-2.6) after adjusting for age, smoking, alcohol consumption, marital status, educational attainment, rank, employment status and civilian or military status on follow-up. It might seem reasonable to assume that our unadjusted summary ORs arising from the meta-analyses might be similarly overestimating the true association between painful symptoms and Gulf deployment.

Strengths and limitations of this review
This review benefits from a sensitive search strategy based on both published material and on grey literature such as conference abstracts and preliminary reports. Furthermore, inclusion and exclusion criteria were independently assessed by two reviewers. However, failure to identify some studies is always a possibility in systematic reviews. The majority of the primary studies that we identified reported Gulf deployment to be independently associated with symptoms of pain. The absence of many studies with negative findings raises the possibility of the existence of publication bias. However in order to affect the weighted summary estimates derived from the meta-analyses, any statistically significant negative results that are currently missing from the review would have to have been based in large study samples and these would have been more likely to be published. Therefore the likelihood of publication bias being present which would actually alter the conclusions of the review is small.
This review could only investigate symptoms of pain in sites reported by the primary studies. Published papers might have been limited to reporting only the most frequently recorded symptoms rather than all measured symptoms [14,21,22,29], and therefore the association between Gulf deployment and symptoms of pain in other unreported sites is unknown. However, given the consistency in the results for all measured sites of pain included in this review, it might seem unlikely that Gulf deployment would have a dramatically different association with any unreported site of pain.
This review has been limited to investigating the association between Gulf deployment versus non-deployment and reporting of pain. We chose not to examine the association between specific environmental exposures of the war (e.g. threat of chemical warfare agents, non-routine immunisations) and reporting of symptoms due to the problems associated with the inaccuracy of such selfreported exposures.
In this review we were not attempting to measure the possible underlying biological or socio-cultural mechanisms which could explain the observed association between Gulf deployment and symptoms of pain. However, the experience of being deployed into a potentially life threatening situation is obviously extremely stressful, and psychological stress can manifest itself in a range of physiological symptoms, including pain [34].

Conclusion
The results of this systematic review support the hypothesis that a higher proportion of veterans of the Persian Gulf War of 1991 have reported symptoms of pain than comparison groups of military personnel. Gulf deployment was most strongly associated with abdominal pain, with Gulf veterans being more than three times more likely to report such pain. However, the methodological quality of the primary studies varied greatly and the summary estimates from meta-analyses were often associated with statically significant heterogeneity. At least some of the observed association might be explained by response bias, measurement bias and confounding. Even if the point estimates of relative risk observed in this review are somewhat inflated due to these limitations of the data, it is still clear that Gulf War veterans continue to suffer from poorly understood painful symptoms many years after returning from the conflict. These findings are consistent with the generally increased reporting of all symptoms (for example multiple chemical sensitivity, chronic fatigue, post traumatic stress disorder, common mental disorder) by veterans of the Gulf War of 1991 when compared to other military groups [7,35].