Effect of chronic opioid use on the hematological and inflammatory markers: A retrospective study from North India.

Background: Chronic opioid use affects biological functioning implicating the hematopoietic and immune system. It may alter various hematological parameters and inflammatory markers. This study aimed to assess the association of opioid dependence with the hematological parameters and inflammatory markers in the Indian population.
Methods: A retrospective chart review was done among opioid dependent (ODS) males and healthy controls (HC) who visited the center's laboratory between Jan 2017 and Dec 2018 for hematological investigations. Clinical records reviewed for opioid use details like type, duration, and route of administration. The hematological profile presented as Mean or median. Mann-Whitney U test was used to compare the hematological parameters between the cases and controls.
Results: The study included 191 ODS patients and 123 controls. Among ODS patients, a significant decrease in the levels of hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin and an increase in RBC count and lymphocytes was observed when compared to controls. The inflammatory markers, Neutrophil-Lymphocyte Ratio (NLR) and Platelet-Lymphocyte Ratio, were significantly lower among ODS. Longer duration of opioid use leads to increased NLR among ODS patients. Opioid use by injection did not alter any of the hematological parameters compared to non-injection drug use.
Conclusion: Chronic opioid use has a significant effect on the hematopoietic cells. Opioid use for longer durations increases the inflammatory markers suggesting underlying infections. Copyright:

INTRODUCTION

Opioid-dependent patients frequently suffer from malnutrition due to poor calorie intake and lack of balanced diet.[123] Thus, they are at high risk of vitamin and mineral deficiencies affecting hematological parameters like Hemoglobin (Hb), Mean Corpuscular Volume (MCV), and Mean Corpuscular Hemoglobin (MCH). They are also at a high risk of infectious diseases like HIV and tuberculosis. Opioids play a modulatory role on immunity and inflammation.[456] They may have anti-inflammatory action in peripheral tissues[7] and pro-inflammatory properties like neuroinflammation.[8] All these factors can, in turn, influence the number and function of white blood cells (WBCs), platelets, as well as inflammatory markers like the Neutrophil to Lymphocyte Ratio (NLR) and Platelet to Lymphocyte ratio (PLR).

Previous studies evaluating the association of opioid dependence with hematological parameters showed mixed results. Few studies observed an increase in relative proportion of lymphocytes[9] and platelets[10] and some reported decrease in number of lymphocytes,[11] platelets,[12] Hb, hematocrit (HTC), and red blood cell (RBC),[13] while few documented no change.[14] The limited studies available on the association of opioid dependence with inflammatory markers pointed toward raised NLR and PLR ratio among ODS as compared to healthy controls,[1516] while most of these studies have predominantly tried to compare the hematological parameters of opioid-dependent subjects with healthy controls. Lu and colleagues assessed the effect of duration of opioid use on hematological parameters.[12] Assessing the effect of duration of opioid use can help to further understand the long-term effects of opioids. There is a dearth of literature from India. A single study from West Bengal, India, reported association of opioid dependence with some blood parameters.[17] In this backdrop, we investigated the association of chronic opioid use and hematological parameters (Complete Blood Count) including inflammatory markers among opioid-dependent population from a leading tertiary care treatment center from North India.

METHODOLOGY

A retrospective chart review was carried out in one of the leading drug dependence treatment facility in north India. The treatment facility caters only to patients seeking treatment for their dug use problem. The study comprised patients with opioid dependence syndrome (ODS) and healthy controls who visited the biochemistry laboratory for their hematological investigation between Jan 2017 and Dec 2018. The biochemistry laboratory carries out the hematological and biochemical testing to assess the health damage due to drug use of all the patients visiting the facility. The institute ethical committee approved the study.

Patients with opioid dependence were included if they were male, aged between 18 and 60 years, and diagnosed as ODS based on International Classification of Diseases—10th revision criteria by a trained psychiatrist. The patients were excluded if the records mentioned dependence on any other substance (except tobacco) or any other medical or psychiatric comorbidity. Control group comprised of male staff and their relatives who visited the laboratory for hematology analysis due to some general medical condition during the study period. Also, the controls were not dependent on any drug as per the clinical records.

From the clinical records, opioid use details like type of opioids, duration of use, and route of administration were collected. In the case of healthy controls, all the details was obtained from the laboratory records (Name, Age, Gender, and Unique ID of patient). The hematological profile collected from the laboratory records includes Red Blood Cell count (RBC), Hemoglobin (HB), Hematocrit, MCV, MCH, Platelet count (PLT), WBC count, Differential Leucocyte count (Neutrophils (NEU), Lymphocytes (LYM), Eosinophils (ESO), and Basophils. These investigations were done using hematology counter (Dx500, Beckman Coulter, India). NLR and PLR were calculated from the obtained laboratory details.

All the statistical analysis were performed using SPSS 21.0 version. The hematological parameters were compared between the ODS patients and healthy controls using Mann–Whitney U test as all the hematological parameters followed non-normal distribution. To assess the effect of duration of opioid use on the hematological parameters and NLR and PLR ratio, ODS patients were divided into two groups: (1) Duration of opioid use less than 7 years and (2) Duration of opioid use more than or equal to 7 years. Mann–Whitney U test was again used to compare the hematological parameters between the two groups. The P value below 0.05 was considered as significant.

RESULTS

The study included 191 opioid-dependent male patients (cases) and 123 healthy controls. The mean (SD) age of the patients and controls were 28.5 (8.8) and 32.2 (10.6) years, respectively.

Clinical details: The median age of onset of opioid use was found to be 18 years (IQR: 14, 23 years). The primary opioid as used by the patients was heroin (92.1%, n = 176) followed by synthetic opioids (4.1%, n = 8) and natural opiates (3.7%, n = 7). At the time of sample collection, majority of the patients were on medications. Nearly one-fourth of the patients (24.6%, n = 47) reported using opioids by injection route. During the study period, the patients (n, %) were on pharmacological interventions like buprenorphine (77, 39.3%), tramadol (40, 20.9%), and naltrexone (52, 27.2%). More than half (57%) of the patients (n = 109) were also receiving benzodiazepines as adjuvant medications along with the above medications. A total of 101 participants were screened for HIV, of whom 13 were positive.

Hematological profile of ODS cases and controls: Among opioid-dependent patients, a significant decrease was observed in blood parameters like Hb, MCV, and MCH, while a significant increase was observed in the RBC count and WBCs (lymphocytes). Although neutrophils showed a decreasing trend among cases, it did not reach statistical significance. There was also a significant difference between the two groups with respect to monocytes and platelets, with the low values among cases compared to controls. Also, the emerging prognostic inflammatory markers, NLR and PLR, were significantly decreased among OUD patients compared to controls [Table 1].

Table 1

Comparison of hematological parameters between ODS patients and controls

Parameter	ODS (n=191)	Control (n=123)	P
WBC (1012/L)	7.8 (6.3, 9.2)	7.6 (6.3, 9.3)	0.79
RBC (1012/L)	4.7 (4.4, 5.1)	4.6 (4.2, 4.9)	0.04*
HB (g/dl)	13.3 (12.4, 14.4)	14.1 (13.1, 15.1)	0.00*
HCT (%)	42.4 (39.8, 46.2)	42.6 (39.0, 45.3)	0.58
MCV (fL)	90 (84.9, 94.5)	92.2 (87.8, 95.4)	0.01*
MCH (pg)	28.2 (26.2, 30.0)	30.9 (29.2, 32.1)	0.00*
PLT (109/L)	181 (155, 221)	194 (153, 227)	0.40
NEU (%)	57 (51, 64)	61 (53, 66)	0.06
LYM (%)	35 (29, 42)	32 (26, 37)	0.00*
ESINO (%)	3 (2, 5)	3 (1, 5)	0.23
MONO (%)	4 (2, 5)	4 (2,7)	0.00*
NLR	1.63 (1.24, 2.18)	1.88 (1.42, 2.46)	0.01*
PLR	71.48 (52.59, 97.16)	84.75 (58.59, 100.99)	0.04*

*Mann–Whitney U test P<0.05

Effect of duration of opioid use: As shown in Table 2, comparison of the hematological parameters based on duration of opioid use indicated a significant increase in the neutrophil count and decrease in the lymphocyte count among patients who used opioids for longer duration (7 years and above). Consequently, the NLR ratio was found to be significantly higher in the group which used opioids for longer duration.

Table 2

Comparison of Hematological parameters between ODS cases with duration of opioid use

Parameter	Total (n=191) Median (IQR)	Group 1(n=94), Median (IQR)	Group 2(n=97), Median (IQR)	Comparison P
Hb	13.3 (12.4, 14.4)	13.3 (12.6, 14.6)	13.1 (12.3, 14.3)	0.177
RBC	4.7 (4.4, 5.1)	4.7 (4.3, 5.2)	4.7 (4.4, 5.0)	0.404
HCT	42.4 (39.8, 46.2)	42.8 (40.1, 46.5)	41.0 (39.0, 45.9)	0.178
MCV	90.2 (84.9, 94.5)	90.7 (85.6, 94.5)	89.3 (84.1, 94.1)	0.318
MCH	28.2 (26.2, 30.0)	28.5 (27.0, 30.2)	27.8 (25.6, 29.8)	0.074
Platelets	181.0 (155.0, 221.0)	184.0 (154.0, 226.5)	177.0 (154.5, 219.5)	0.617
TLC	7.8 (6.3, 9.2)	7.45 (6.2, 8.6)	8.1 (6.4, 9.6)	0.066
Neutrophil	57.0 (51.0, 64.0)	55.5 (50.0, 60.3)	59.0 (53.0, 66.0)	0.005*
Lymphocyte	35.0 (29.0, 42.0)	37.0 (32.0, 44.0)	33.0 (27.0, 39.0)	0.000*
Eosinophil	3.0 (2.0, 5.0)	3.0 (2.0, 4.3)	3.0 (2.0, 5.0)	0.461
Monocyte	4.0 (2.0, 5.0)	4.0 (2.0, 5.0)	3.0 (2.0, 4.5)	0.535
NLR ratio	1.63 (1.24, 2.18)	1.6 (1.1, 1.9)	1.85 (1.4, 2.4)	0.001*
PLR ratio	71.48 (52.6, 97.2)	71.3 (53.9, 91.2)	72.1 (50.1, 105.7)	0.508
MCH	27.99 (3.02)	28.32 (2.61)	27.67 (3.36)	0.137 (t=1.494)#

Group 1 (less than seven years), Group 2 (duration of opioid use seven years and above). Mann–Whitney U test *P<0.05, #Independent sample t-test

Effect of injection drug use: The study also compared the parameters between injection drug users and non-injection drug users among the opioid-dependent patients. There was no significant difference observed in any of the hematological parameters between the two groups, as can be seen from Table 3.

Table 3

Comparison of Hematological parameters between ODS cases who have ever used opioids by injection use and ODS cases who never injected

Parameter	IDU ever (n=47) Median (IQR)	Non-IDU (n=144) Median (IQR)	Comparison P
Hb	13.0 (12.3, 14.2)	13.3 (12.4, 14.5)	0.208
HCT	41.4 (39.3, 45.9)	42.5 (39.8, 46.4)	0.337
MCV	88.3 (81.8, 93.5)	90.6 (86.3, 94.7)	0.095
MCH	27.3 (25.4, 29.6)	28.4 (26.5, 30.2)	0.074
Platelets	167 (135.0, 219.0)	184.0 (156.3, 221.8)	0.115
TLC	7.4 (5.9, 9.1)	7.9 (6.4, 9.3)	0.277
Lymphocyte	35.0 (30.0,40.0)	35.0 (28.0, 42.0)	0.979
Eosinophil	3.0 (2.0, 5.0)	3.0 (2.0, 5.0)	0.246
Monocyte	4.0 (2.0, 5.0)	4.0 (2.0, 4.75)	0.838
NLR ratio	1.6 (1.3, 2.1)	1.6 (1.2, 2.3)	0.872
PLR ratio	67.7 (47.3, 95.7)	72.9 (52.9, 99.6)	0.292
MLR ratio	0.1 (0.06, 0.14)	0.1 (0.07, 0.13)	0.699
RBC	4.7 (0.57)	4.7 (0.67)	0.70 (t=-0.38)
Neutrophil	57.9 (8.7)	58.2 (9.6)	0.85 (t=-0.20)

Mann Whitney U test. *P<0.05, #Independent sample t-test

DISCUSSION

The present chart review examined the changes in the hematological parameters and inflammatory markers due to chronic opioid use. The study included only male patients in the 18 to 60 years age group due to the following reasons: (1) Opioid dependence is more common among males,[18] (2) most of the treatment seeking ODS patients visiting the center belong to this age group, and (3) hematological parameters are influenced by age and sex.[19] Hence, restricting the sample to this demographic profile helped in reducing the bias caused by age and sex. Most of the cases used heroin, followed by pharmaceutical opioids and natural opiates, similar to the pattern seen among opioid users in a recent national survey.[18]

A significant decrease in the Hb, MCV, and MCH values and an increase in RBC count among ODS patients was observed. The decrease in Hb, MCV, and MCH levels are in agreement with reports of low Hb and serum iron levels among heroin smokers.[131415] The decrease in MCV and MCH could be explained by iron deficiency among ODS patients due to poor nutrition. However, due to unavailability of iron status, it cannot be firmly established. Also with iron deficiency, there should have been a proportionate reduction in RBC count. However, this study found an increase in the RBC count that might be contributed by the concurrent tobacco use prevalent among 94.1% of the cases. Tobacco is known to cause an increase in the RBC count, MCV, MCH, and Hb. 20 Hence, the interaction of tobacco use, nutritional deficiency, and opioid use could have contributed to the mixed picture in our case. Literature provide mixed results with no significant effect of opioid use on RBC parameters among opioid dependent patients.[1718192021] This study reported no significant effect of duration of opioid use on RBC parameters, similar to the study by Lu and colleagues.[12]

WBCs, especially neutrophils and lymphocytes, play an important role in immunity as well as inflammation. Opioids plays immunomodulatory role and its chronic use is associated with higher risk of infections.[22] Hence, the combination of infections and immunomodulatory effects may lead to changes in WBCs levels. This study reported a significant increase in lymphocyte and no change in neutrophil level among ODS patients. However, the effect of duration of opioid use indicated opposite trend. With increase in duration of opioid use, a decrease in lymphocytes and increase in neutrophils was observed. Mixed results reported earlier with both increase[1721] and decrease in lymphocytes[15] and neutrophil count among opioid-dependent patients.[1715] Previous report did not observe any effect of duration of opioids use on WBCs.[12] These variations may be due to either direct or indirect action of opioids, comorbid infections, substance use, and withdrawal status. Direct action of chronic opioid use on lymphocytes reduces its proliferative capacity thereby reducing its levels.[23] At the same time, the presence of comorbid infections as well as other confounders like tobacco use can increase the lymphocytes[172425] causing the variations in our results. Also, withdrawal state may influence the levels of neutrophils and lymphocytes among opioid-dependent patients.[10] Around one-fourth (27.2%) of the patients were on naltrexone, while 60.2% of the patients were on opioid medications (buprenorphine or tramadol) at the time of sample collection. However, the withdrawal status of the patient could not be reliably established at the time of blood sample collection. Also, smoking is known to affect the level of WBCs. Among the other WBCs, a significant reduction in monocytes was observed among opioid-dependent patients which is similar to previous studies.[1017] Platelets plays important role in blood clotting and immunity and inflammation.[26] Chronic drug use including opioid dependence may cause damage to platelets causing distinct morphological changes in platelets including reduction in number.[27] Thrombocytopenia is known to occur among active heroin users.[28] Previous studies have found a reduction in the platelets with longer duration of opioid use.[12] Our study also found a decreasing trend in platelets among patients with longer duration of opioid use compared to shorter duration, though it did not reach statistical significance. However, conflicting findings were observed by few studies with either no change or increase in the number of platelets among patients with opioid dependence.[1421]

The inflammatory markers, NLR and PLR, were lower among ODS patients compared to controls in the current study. However, their values were high among patients with longer duration of opioid. The previous studies found a significant increase of NLR and PLR among opioid-dependent patients.[152129] Most of these studies predominantly involved active heroin or opium users. In this study, most of the patients were on treatment. This could be one of the reasons for the contrasting findings. Also, as mentioned earlier, the withdrawal status and abstinence status of the patient and its influence on these values is not known. The increase in NLR and PLR ratios among people with longer duration of opioid use compared to those with shorter duration of opioid use is similar to previous studies[29] and may reflect chronic inflammation due to opioid use.

This study adds to the limited number of studies from India that has tried to assess the impact of opioid use on the hematological parameters and inflammatory markers among opioid-dependent patients. Since this is a retrospective chart review study, few confounders are beyond control like current drug use and withdrawal status of the patient that may influence the hematological parameters. Also, the effect of comorbid drug use and pharmacological treatment could not be ruled out. In addition, the controls were not necessarily healthy when they visited the laboratory. However, even with these limitations, the study shows a definite association of hematological parameters with opioid use, which is further substantiated by significant difference based on the duration of opioid use. In future, prospective studies after controlling for confounders are warranted.

CONCLUSION

The study found a significant impact of opioid dependence on hematological parameters like Hb, MCV, and MCH, indicating a direct or indirect effect on the hematopoietic cell. A significant decrease in the inflammatory markers like neutrophil, platelets, and monocytes may suggest a suppressed immune response. Longer duration of opioid use leads to an increase in the NLR indicating subclinical infections.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.