INTRODUCTION:

The word "pain" is derived from the Latin word "poena" meaning a penalty. McBeth and Jones¹ suggested that pain can indicate the severity of an underlying condition. International Association for the Study of Pain defined pain as- “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.²Pain is a major clinical, socioeconomic issue in communities throughout the world. Pain can affect emotional and mental wellbeing. In recent years, impact of gender and obesity on pain perception have been received significant pragmatic attention.

There is no one standard dose or specific medication that will provide adequate analgesia to all patients. Nowadays, the optimal current approach is to titrate analgesics to produce optimal therapeutic benefit.³It is usually accepted that males and females also obese and lean individuals respond differently to painful conditions. Obesity may lead to pain because of excess mechanical stress and its pro-inflammatory state. Endocrine changes associated with obesity may be responsible for the difference in the pain threshold. Leptin is secreted by adipocytes in proportion to the amount of body fat and exerts a potent inhibitory action on food intake. In humans, serum leptin concentrations correlate positively with percent body fat.^4-11 In addition, leptin plays a significant permissive role in the physiological regulation of several neuroendocrine axes, including the hypothalamic-pituitary-gonadal,-thyroid, -growth hormone, and -adrenal axes.¹² It is not known whether obesity causes chronic pain, chronic pain causes obesity or some other factor causes both concurrently.

Differences in pain thresholds may have implications in pain management, as they may account in part for the variability in analgesic requirements between individuals. The combination of a probable increased pain perception and a decreased effect of pain medication make obese subjects a group of patients with high healthcare consumption. Thus, to establish an interrelationship among pain, opioids, gender and obesity is the focus of a growing body of research. Consequently, this systematic review was aimed to analyse the impact of gender and obesity on pain perception.

METHODOLOGY:

This systematic review has been conducted in accordance with the PRISMA guidelines (an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses for systematic reviews).

Search Strategy:

The Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and EMBASE were searched from their inception to the year 2019. We used the following key terms and their synonyms, truncated where necessary: gender, sex hormones, obesity, body mass index, leptin, analgesic requirements, endogenous opioids, pain measurement, and pain perception/sensitivity/threshold. Grey literature was also searched, and a reference crosscheck was performed to detect eligible articles that were not identified through prior searches. The search was conducted without restrictions on language or publication date.

Study Eligibility Criteria:

Types of Studies:

Included:

We included pre-clinical studies, randomized, controlled trials (RCTs), prospective and retrospective cohort studies, and case-control studies. RCTs and non-randomized studies directly compared the interventions of interest. For non-randomized studies, we included prospective as well as retrospective studies.

Excluded:

We excluded descriptive studies, cross-sectional studies, case series, and case reports because of the lower level of evidence.

Literature Search:

Pain versus Gender:

Gender related influence on perception of pain and efficacy of analgesics has received more attention in these days.^13-25 Fillingim¹³ reported that women experience more pain compared to men. Gender differences is not limited to pain perception but may extend to the response to analgesics. Riley et al²⁶ found that women experience more intensity of postoperative pain and less tolerance to pain in comparison with men. Rosseland et al²⁷ reported gender difference in response to analgesic action of opioids, but the findings were inconsistent. Some of the studies reported that following administration of mixed opioid agonist antagonists, female patients experienced better analgesic efficacy compared to males, whereas others reported that following morphine administration females required an increased dose compared to males to achieve analgesia of the same degree.^28-31 Walkers et al³² and Zammataro et al³³ reported the gender difference in response to non-opioid analgesics. Cruz et al³⁴found that female gonadal hormones have an important impact on many brain functions like pain perception. Hussain et al³⁵ reported that following laparoscopic cholecystectomy, females experienced more pain and required higher doses of opioid analgesics compared to males. Some of the studies have reported conflicting results for influence of gender on pain perception and the requirements of analgesics for pain relief to similar degree of analgesia.^17-21,25 This could be due to type of surgery, different types of analgesic drugs, different methods of pain relief, and duration of treatment. Chia et al³⁶ reported increased sensitivity to postoperative pain and morphine requirements by men compared to women. Mattila et al³⁷ reported that following arthroscopic knee joint surgery pain scores were higher in females compared to males. Rosseland et al²⁷ and Taenzer et al³⁸ found that more percentage of females reported pain as compared to males in patients undergoing knee arthroscopic surgery, but there was no significant difference in pain scores between both the genders. Lau et al³⁹ found that following endoscopic hernioplasty, pain scores were significantly increased in females compared to males. Palmeira et al⁴⁰ reported that women experience more pain to noxious stimuli compared to men. The differences in pain perception related to sex may be associated with hyperalgesia in women, but also to the hypo activity of the inhibitory system of pain in females. Biological factors such as sex hormones are thought to be one of the foremost mechanisms which explain sex differences in pain perception.^41-47 Some of the studies suggested that central mu-opioid receptor concentrations differ between men and women, which is probably regulated by age and circulating gonadal steroids.^48,49 Cicero et al⁵⁰ suggested that endogenous opioid system is modulated by estrogen and testosterone. Some of the studies acclaimed that gonadal steroid hormones can influence sensitivity to analgesia during development of the organism (organizational effects) and/or during adulthood (activational effects).^49-51 Some of the studies conveyed that pain is reported more frequently by women than by men across multiple geographic regions.^52-54

Some of the studies reported that influence of sex hormones represents a significant source of pain-related variability that likely impacts men and women differently.^41-47,55-58 Thompson et al⁴⁴ reported the modulation of endogenous opioid system by estrogen and testosterone. Claiborne et al⁵⁹ reported that estrogen diminishes OFQ-induced anti-nociception, including suppression of ORL1 (opioid receptor-like) receptor expression and its coupling to G-proteins which would secondarily modify the affinity of OFQ to the ORL1 receptor leading to increased pain sensitivity against noxious stimuli. Claiborne et al⁵⁹ also reported that testosterone upregulates expression of the ORL1 gene and enhances coupling of OFQ receptors to (Gi/Go) proteins leading to decreased pain sensitivity against noxious stimuli.

Pain versus Obesity:

Nowadays, pain and obesity are considered as the major public health issues globally. Some of the studies have reported that pain sensation increases with an increase in body mass index.^16,17,60-63 Obesity increases serum leptin levels due to more adipose tissues which can affect pain threshold, emotional mood, and quality of life. Younger et al⁶⁴suggested that increased systemic leptin concentration might be associated with more sensation sensitivity to pain perception. Lloret et al⁶⁵have reported the variations in pharmacokinetics of morphine among obese patients. Mc Kendall et al⁶⁶ conducted a study based on the hypothesis claiming that endogenous opioids are increased in obese individuals. They applied a constant pressure of approximately three pounds to the tip of the thumb on fifty-six obese and non-obese patients to measure the time interval until the first sensation of pain. However, contrary to the expectations, the obese patients were found to be more sensitive to pain.⁶⁶Roane and Porter⁶⁷ found that obese (fa/fa) Zucker rats (genetically obese rats) were more sensitive to pain against tail flick pain stimulation tests. Some of the studies have reported that persistent pain problems are very common in obese individuals.^68-72Miscio et al⁷³ reported more pain sensitivity in obese group in comparison with non-obese group but they could not find direct correlation between body mass index and pain threshold. Ramzan et al⁷⁴ employed hot water as a pain stimulant on obese and non-obese rats before measuring the pain threshold by tail flick test and found that tail flick latency was 30% higher in obese rats. Ensari et al⁷⁵ reported that decreasing ghrelin levels in obesity might have an impact on pain sensitivity. Ghrelin was noted to have an excitatory effect on neurons containing endogenous opioid, reduce pain via its anti-inflammatory influence, and act as an anti-nociceptive agent in association with the endocannabinoid system.⁷⁵ Zahorska-Markiewicz et al⁷⁶ tested pain sensitivity using electrophysiological method in obese and control women and reported that pain threshold was higher in obese than the control subjects but weight reducing treatment did not change the pain sensitivity in obese women. Pradalier et al⁷⁷ reported a less requirement for narcotic analgesics among postoperative obese patients.

Khimich⁷⁸ evaluated the pain threshold of patients using pin prick test and reported that obese females experienced less pain sensation than normal females and females with a low body mass index (BMI). Obese patients with a binge-eating disorder have been observed to have higher pain threshold values than normal individuals and obese patients with no binge-eating disorder.⁷⁹This remarkable difference was associated with the antinociceptive response generated by excessive vagal activation in binge-eating disorder.⁷⁹ Maffiuletti et al⁸⁰ evaluated motor and sensory excitability threshold and found higher sensory and motor thresholds in obese compared to non-obese subjects.

Dodet et al⁸¹ found that sensitivity and pain detection thresholds were more in obese than in non-obese population. They also reported that sensory dysfunction and pain detection thresholds were not correlated with weight loss, hormonal and genetic factors. Nordander et al⁸² evaluated the excitability of the trapezius muscle using surface electromyography and found a significant decrease in electromyography amplitudes in response to increasing thickness of subcutaneous adipose tissue.

Many of the aforementioned studies on humans involve low number of cases and wide range of age.^76-82 Furthermore, they did not mention whether the patients had pain before the test or had any disease that would cause pain. In addition, these studies have applied only one measurement from only the upper extremities. The contradictory results may be explained by these factors. Some of the studies recommended that among approximately 15% of the Dutch inhabitants and 36% of the Americans, the chance of surgery on an obese subject is greater and therefore also the chance to be exposed to different kind of pain levels during surgery is more.^83-85

The combination of a probable increased pain perception and a decreased effect of pain medication make obese subjects a group of patients with high healthcare consumption. Lim et al⁸⁶ and Maeda et al⁸⁷ reported the role of leptin in nociceptive behavior. Glutamate is an excitatory neurotransmitter which stimulates N-methyl-D-aspartate (NMDA) receptors (a sub-type of glutamate receptors). Lim et al⁸⁶ reported that central effect of leptin on neuropathic pain is possibly due to the up-regulation of NMDA receptors. Maeda et al⁸⁷ reported that macrophage stimulation by leptin led to peripheral pain. The exact cellular mechanism for nociceptive behavior of leptin is still unclear. Alpha-melanocyte stimulating hormone (α-MSH) is an endogenous peptide hormone and neuropeptide of the melanocortin family. Selim et al⁸⁸ and Dunbar et al⁸⁹ reported that leptin regulates the secretions of alpha-MSH and beta-endorphin. Starowicz and Przewłocka⁵ suggested that α-MSH acts as endogenous anti-opiate. Rene et al⁹⁰and Vrinten et al⁹¹ reported that α-MSH stimulates the activity of adenylate cyclase where as β-endorphins inhibits the activity of adenylate cyclase. Some of the studies reported that leptin mediated activation of NMDA receptors lead to more pain sensation.^92-95 Some of the studies reported that blocking the NMDA receptors reduces experience of pain sensation following nerve injury.^96-100

Based on these reports, we suggest that obese individuals have more leptin concentration because of more adipose tissues which increases pain sensitivity against noxious stimuli by various mechanisms like up-regulation and/or stimulation of NMDA receptors and/or augmenting α-MSH mediated anti-opiate action and/or macrophage stimulation.

Interrelationship between Sex hormones & Leptin:

Some of the studies suggest that sex hormones can play important role in regulation of leptin secretion.^101-105 Karim et al¹⁰⁶ reported that leptin concentration is positively correlated with estradiol concentration regardless of obesity status in postmenopausal women. Some of the studies reported that there is more leptin levels in females compared to males for the same BMI.^107,108 Some of the studies found that serum leptin concentration increases with increase in subcutaneous fat mass.^109-114 Casabiell et al¹¹⁵ reported more secretion of leptin by adipocytes from women compared to men. High amount of fat mass especially subcutaneous fat could be the possible reason for more serum leptin concentrations in women. Schwartz et al¹¹⁶ suggested that even for a constant plasma leptin level, women have higher cerebrospinal leptin levels possibly due to more leptin transport into the cerebrospinal fluid. Sivan et al¹¹⁷ and Kristensen et al¹¹⁸ reported that estrogen stimulates leptin secretion from adipocytes. Lahlou et al¹¹⁹ found that estrogen stimulates leptin secretion only in adipocytes of women and not in adipocytes of men. Kristensen et al¹¹⁸ and Shimizu et al¹²⁰ reported that leptin levels are decreased in ovariectomized rats, and reversed to normal by exogenous estradiol administration. Some of the studies found that exogenous leptin administration results in earlier onset of puberty in normal female mice.^121,122 Montague et al¹¹³ and Wabitsch et al¹²³ reported that mRNA expression for leptin is less in obese males compared to obese females. Some of the studies reported that testosterone suppresses leptin mRNA expression and reduces leptin secretion by human adipocytes.^123-126 Behre et al¹²⁷ found that hypogonadal men have elevated leptin levels. Jockenhovel et al¹²⁸reported that testosterone supplementation reduces leptin levels. Many studies have reported the inverse correlation between leptin and testosterone levels in men.^{123,127,129-132}

Based on these reports to establish an interrelationship between sex hormones and leptin, we suggest that estrogen has positive correlation and testosterone has negative correlation with leptin levels whereas leptin do not affect the level of sex hormones like estrogen/testosterone.

Summary of Results of Literature Search:

Following extensive literature search, we found that pain sensitivity against noxious stimuli is more experienced in obese as well as females (probably due to more leptin & more estrogen respectively) whereas it is less experienced in lean as well as males (probably due to less leptin & more testosterone respectively). We also found that sex hormones have influence on leptin levels whereas leptin do not affect the level of sex hormones.

CONCLUSION:

This review reveals that from gender perspective sex hormones and from obesity perspective leptin play an important interlinked role in pain modulation. Additional research to elucidate the mechanisms driving sex hormones and leptin in pain perception is needed in order to foster future interventions to reduce disparities in pain. Gender and body mass index specific tailoring of pain treatments might become a conceivable outcome in the foreseeable future.

ACKNOWLEDGEMENT:

The authors are grateful to the Manipal Academy of Higher Education, Manipal, Karnataka (India) for providing the support to conduct this systematic review.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. McBeth J, Jones K. Epidemiology of chronic musculoskeletal pain. Best Pract Res Clin Rheumatol 2007;21(3):403-425.

2. International Association for the Study of Pain. IASP taxonomy. http://www.iasppain.org/Taxonomy?&navItemNumber=576. Updated October 20, 2014.

3. Nasir M, Parveen RA, Alam NN. Pattern of Analgesic Use in Post-Operative Pain Management in a Tertiary Level Teaching Hospital in Bangladesh. Research Journal of Pharmacy and Technology. 2016; 9(5): 493-496.

4. Mewada PS, Patel CK, Rami CS, Patel HU, Patel CN. New Emerging Targets for Obesity. Asian Journal of Research in Chemistry. 2010; 3(2): 278-287.

5. Amin SS. Obesity Prevalence in Primary School Children in Baghdad City. Research Journal of Pharmacy and Technology. 2019;12(1): 339-41.

6. Nadar S. Side effects of Obesity-A Review. Research Journal of Pharmacy and Technology 2015;8(8):979-986.

7. Reshmi B, Sethu G. A Study on Obesity among Children. Research Journal of Pharmacy and Technology. 2015;8(8):1177-1178.

8. Baheerati MM, Devi RG. Obesity in relation to Infertility. Research Journal of Pharmacy and Technology 2018;11(7):3183-3185.

9. Mohsen H, Shaden H, Faiza AL, Taghrid H. Correlation of serum leptin levels with insulin resistance in Syrian obese patients with type 2 diabetes mellitus. Research Journal of Pharmacy and Technology. 2013; 6(10): 1149-1151.

10. Mohan M. The Role of Leptin on Obesity: A Review. Research Journal of Pharmacy and Technology. 2014;7(12):1501-1505.

11. Monalisa R. Role of leptin in obesity. Research Journal of Pharmacy and Technology. 2015;8(8):1073-1076.

12. Al-Ogaidi SO, Abdulsattar SA, Al-Dulaimi HM. The Impact of Serum Leptin, Leptin Receptor and Insulin on Maternal Obesity. Research Journal of Pharmacy and Technology. 2019;12(7):3569-3574.

13. Fillingim RB. Sex differences in analgesic responses: evidence from experimental models. Eur J Anaesthesiol. 2002;19(Suppl. 26):16-24.

14. Isacson D, Bingefors K. Epidemiology of analgesic use: a gender perspective. Eur J Anaesthesiol 2002;19(Suppl. 26):5-15.

15. Starowicz K, Przewlocka B. The role of melanocortins and their receptors in inflammatory processes, nerve regeneration and nociception. Journal of Life Sciences. 2003;73:823-847.

16. Priyanka V, Rekha V. Analgesic, anti-inflammatory and antipyretic activity of Cissus quadrangularis. Journal of Pharmaceutical Science and Technology 2010;2(1):111-118.

17. Maria TC, Cenzo C, Valentina O, Micaela M, Omar C. Synthesis of ibuprofen heterocyclic amides and investigation of their analgesic and toxicological properties. European Journal of Medicinal Chemistry. 2003;38:513-518.

18. Bicer F, Eti Z, Aricioglu F, Konya D, Gogus Y. The effects of gabapentin, tramadol and amitriptyline on pain behavior in a rat neuropathic pain model: 14AP10-2. European Journal of Anaesthesiology 2010;27(47):217.

19. Kvachadze I, Tsagareli MG, Dumbadze Z. An overview of ethnic and gender differences in pain sensation. 2015;238:102-108.

20. Rovner GS, Sunnerhagen KS, Bjorkdahl A, Gerdle B, Borsbo B, Johansson F et al. Chronic pain and sex-differences; women accept and move, while men feel blue. PLoS One. 2017;12(4):e0175737 (online).

21. Eltumi HG, Tashani OA. Effect of Age, Sex and Gender on Pain Sensitivity: A Narrative Review. The Open Pain Journal. 2017;10:44-55.

22. Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Tayes S, Alexander JK et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015; 18(8): 1081-1083.

23. Feijo LM, Tarman GZ, Fontaine C, Harrison R, Johnstone T, Salomons T. Sex-specific effects of gender identification on pain study recruitment. The Journal of Pain. 2018;19(2):178-185.

24. Manubay J, Davidson J, Vosburg S, Jones J, Comer S, Sullivan M. Sex differences among opioid-abusing chronic pain patients in a clinical trial. J Addict Med. 2015;9(1):46-52.

25. Koons AL, Greenberg MR, Cannon RD, Beauchamp GA. Women and the experience of pain and opioid use disorder: A literature-based commentary. Clinical Therapeutics. 2018;40(2):190-196.

26. Riley JL, Robinson ME, Wise EA, Myers CD, Fillingim RB. Sex differences in the perception of noxious experimental stimuli: A meta-analysis. Pain. 1998;74:181-187.

27. Rosseland LA, Stubhaug A. Gender is a confounding factor in pain trials: Women report more pain than men after arthroscopic surgery. Pain 2004;112:248-253.

28. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD. Kappaopioids produce significantly greater analgesia in women than in men. Nat Med. 1996;2:1248-1250.

29. Gear RW, Gordon NC, Heller PH, Paul S, Miaskowski C, Levine JD. Gender difference in analgesic response to the kappa-opioid pentazocine. Neurosci Lett. 1996;205(3):207-209.

30. Cepeda MS, Carr DB. Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesth Analg. 2003;97:1464-1468.

31. Aubrun F, Salvi N, Coriat P, Riou B. Sex and age related differences in morphine requirements for postoperative pain relief. Anesthesiology. 2005; 103: 156-160.

32. Walkers JS, Carmody JJ. Experimental pain in healthy human subjects: Gender differences in nociception and in response to ibuprofen. Anesth Analg. 1998; 86: 1257-1262.

33. Zammataro M, Merlo S, Barresi M, Parenti C, Hu H, Sortino MA et al. Chronic treatment with fluoxetine induces sex-dependent analgesic effects and modulates HDAC2 and MGLU2 expression in female mice. Front. Pharmacol. 2017;8:743 (online).

34. Cruz WS, Pereira LA, Cezar LC, Camarini R, Felicio LF, Bernardi MM. Role of steroid hormones and morphine treatment in the modulation of opioid receptor gene expression in brain structures in the female rat. Springer Plus. 2015;4:355 (online).

35. Hussain AM, Khan FA, Ahmed A, Chawla T, Azam SI. Effect of gender on pain perception and analgesic consumption in laparoscopic cholecystectomy: An observational study. J Anaesthesiol Clin Pharmacol. 2013;29(3):337-341.

36. Chia YY, Chow LH, Hung CC, Liu K, Ger LP, Wang PN. Gender and pain upon movement are associated with the requirements for postoperative patient controlled iv analgesia: A prospective survey of 2,298 Chinese patients. Can J Anaesth. 2002;49:249-255.

37. Mattila K, Toivonen J, Janhunen L, Rosenberg PH, Hynynen M. Post-discharge symptoms after ambulatory surgery: First week incidence, intensity, and risk factors. Anesth Analg. 2005;101:1643-1650.

38. Taenzer AH, Clark C, Curry CS. Gender affects report of pain and function after arthroscopic anterior cruciate ligament reconstruction. Anesthesiology. 2000; 93: 670-675.

39. Lau H, Patil NG. Acute pain after endoscopic totally extraperitoneal (TEP) inguinal hernioplasty: Multivariate analysis of predictive factors. Surg Endosc. 2004;18:92-96.

40. Palmeira CC, Ashmawi HA, Posso Ide P. Sex and Pain Perception and Analgesia. Rev Bras Anestesiol. 2011;61:6:814-828.

41. Tousignant-Laflamme Y, Marchand S. Excitatory and inhibitory pain mechanisms during the menstrual cycle in healthy women. Pain. 2009; 146:47

42. Fillingim RB, Gear RW. Sex differences in opioid analgesia: clinical and experimental findings. Eur J Pain. 2004;8:413-425.

43. Gaumond I, Arsenault P, Marchand S. Specificity of female and male sex hormones on excitatory and inhibitory phases of formalin-induced nociceptive responses. Brain Res. 2005;1052:105-111.

44. Thompson AD, Angelotti T, Nag S, Mokha SS. Sex-specific modulation of spinal nociception by alpha-adrenoceptors: differential regulation by estrogen and testosterone. Neuroscience. 2008; 153: 1268-1277.

45. Hagiwara H, Kimura F, Mitsushima D, Funabashi T. Formalin-induced nociceptive behavior and c-Fos expression in middle-aged female rats. Physiol Behav. 2010;100:101-104.

46. Berkley KJ. Sex differences in pain. Behav Brain Sci. 1997;20:371-380.

47. Hurley RW, Adams MCB. Sex, gender and pain: an overview of a complex field. Anesth Analg. 2008;107:309-317.

48. Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM et al. Muopioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci. 2002;22:5100-5107.

49. Zubieta JK, Dannals RF, Frost JJ. Gender and age influences on human brain mu-opioid receptor binding measured by PET. Am J Psychiatry. 1999;156:842-848.

50. Cicero TJ, Nock B, O’Connor L, Meyer ER. Role of steroids in sex differences in morphine-induced analgesia: activational and organizational effects. J Pharmacol Exp Ther. 2002;300:695-701.

51. Wiesenfeld-Hallin Z. Sex differences in pain perception. Gender Med. 2005; 2:137-145.

52. Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley JL. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009;10:447–85.

53. Gerdle B, Bjork J, Coster L, Henriksson K, Henriksson C, Bengtsson A. Prevalence of widespread pain and associations with work status: a population study. BMC Musculoskeletal Disorders. 2008;9:102-106.

54. Mogil JS. Sex differences in pain and pain inhibition: multiple explanations of a controversial phenomenon. Nat Rev Neurosci. 2012;13:859-66.

55. Craft RM. Modulation of pain by estrogens. Pain. 2007;132:S3–S12.

56. Craft RM, Mogil JS, Aloisi AM. Sex differences in pain and analgesia: the role of gonadal hormones. Eur J Pain. 2004;8:397-411.

57. Smith YR, Stohler CS, Nichols TE, Bueller JA, Koeppe RA, Zubieta JK. Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women. J Neurosci. 2006; 26: 5777-5785.

58. Cairns BE, Gazerani P. Sex-related differences in pain. Maturitas. 2009; 63: 292-296.

59. Claiborne J, Nag S, Mokha SS. Activation of opioid receptor like-1 receptor in the spinal cord produces sex-specific antinociception in the rat: estrogen attenuates antinociception in the female, whereas testosterone is required for the expression of antinociception in the male. The Journal of Neuroscience. 2006; 26(50): 13048-13053.

60. Ting-Ting Z, Zhen L, Ying-Li L, Jing-Jing Z, Dian-Wu L, Qing-Bao T. Obesity as a risk factor for low back pain: A meta-analysis. Clinical Spine. Surgery. 2018;31(1):22-27.

61. Okifuji A, Hare BD. The association between chronic pain and obesity. Journal of Pain Research 2015;8:399-408.

62. Song Z, Xie W, Chen S, Strong JA, Print MS, Wang JI et al. High-fat diet increases pain behaviors in rats with or without obesity. Scientific Reports. 2017;7(1):10350.

63. Tashani OA, Astita R, Sharp D, Johnson MI. Body mass index and distribution of body fat can influence sensory detection and pain sensitivity. Eur J Pain. 2017;21(7):1186-1196.

64. Younger J, Kapphahn K, Brennan K, Sullivan SD, Stefanick ML. Association of leptin with body pain in women. J Women’s Health (Larchmt). 2016;25(7):752-760.

65. Lloret LC, Decleves X, Oppert JM, Basdevant A, Clement K, Bardin C et al. Pharmacology of morphine in obese patients: clinical implications. Clin Pharmacokinet. 2009;48:635-651.

66. Mc Kendall MJ, Haier RJ. Pain sensitivity and obesity. Psychiatry Research. 1983;8:119-125.

67. Roane DS, Porter JR. Nociception and opioid-induced analgesia in lean (Fa/-) and obese (fa/fa) Zucker rats. Physiology Behavior. 1986; 38: 215-218.

68. Higgins DM, Kerns RD, Brandt CA, Haskell SG, Bathulapalli H, Gilliam W et al. Persistent pain and comorbidity among operation enduring freedom/operation Iraqi freedom/operation New Dawn veterans. Pain Med. 2014;15(5):782-790.

69. Deere KC, Clinch J, Holliday K, McBeth J, Crawley EM, Sayers A et al. Obesity is a risk factor for musculoskeletal pain in adolescents: findings from a population-based cohort. Pain. 2012; 153(9): 1932-1938.

70. Hoftun GB, Romundstad PR, Rygg M. Factors associated with adolescent chronic non-specific pain, chronic multisite pain, and chronic pain with high disability: The Young-HUNT Study. 2008. J Pain. 2012;13(9):874-883.

71. Smith SM, Sumar B, Dixon KA. Musculoskeletal pain in overweight and obese children. Int J Obes (Lond). 2014;38(1):11-15.

72. Hitt HC, McMillen RC, Thornton-Neaves T, Koch K, Cosby AG. Comorbidity of obesity and pain in a general population: results from the Southern Pain Prevalence Study. J Pain. 2007;8(5):430-436.

73. Miscio G, Guastamacchia G, Brunani A, Priano L, Baudo S, Mauro A. Obesity and peripheral neuropathy risk: a dangerous liaison. J Peripher Nerv Syst. 2005;10:354-358.

74. Ramzan I, Wong BK, Corcaron BG. Pain sensitivity in dietary-induced obese rats. Physiology Behavior. 1993;54: 433-445.

75. Ensari G, Gumustekin M, Ates M. Possible involvement of ghrelin on pain threshold in obesity. Medical Hypotheses. 2010;74:452-464.

76. Zahorska-Markiewicz B, Zych P, Kucio C. Pain sensitivity in obesity. Acta Physiol Pol. 1988;39:183-187.

77. Pradalier A, Dry J, Willer JC, Boureau F. Obesite et baisse du seuil nociceptif. Pathol Biol. 1980;28: 462-474.

78. Khimich S. Level of sensitivity of pain in patients with obesity. Acta Chir Hung. 1997;36:166-177.

79. Raymond NC, de Zwaan M, Faris PL, Nugent SM, Achard DM, Crosby RD et al. Pain thresholds in obese binge-eating disorder subjects. Biol Psychiatry. 1995;37:202-214.

80. Maffiuletti NA, Morelli A, Martin A, Duclay J, Billot M, Jubeau M et al. Effects of gender and obesity on electrical current thresholds. Muscle Nerve. 2011;44:202-207.

81. Dodet P, Perrot S, Auvergne L, Hajj A, Simoneau G, Decleves X et al. Sensory impairment in obese patients? Sensitivity and pain detection thresholds for electrical stimulation after surgery-induced weight loss, and comparison with a non-obese population. Clin J Pain. 2013; 29(1): 43-49.

82. Nordander C, Willnerr J, Hansson GA, Larsson B, Unge J, Granguist L et al. Influence of subcutaneous fat layer, as measured by ultasound, skinfold calipers and BMI, on the EMG amplitude. Eur J Appl Physiol. 2003;89:514-519.

83. Clinical Guidelines in the identification, evaluation and treatment of overweight and obesity in adults, the evidence report, national institutes of health. Obes Res. 1998;6(suppl 2):51S-209S.

84. Allison, D.B., Fontaine, K.R., Manson, J.E., Stevens, J.,Vanitalie, T.B. Annual deaths attributable to obesity in the United states. JAMA. 1999; 282: 1530-1538.

85. World Health Organization. Obesity and overweight. Available at: http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/.2010

86. Lim G, Wang S, Zhang Y, Tian Y, Mao J. Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents. J Clin Invest. 2009;119:295-304.

87. Maeda T, Kiguchi N, Kobayashi Y, Ikuta T, Ozaki M, Kishioka S. Leptin derived from adipocytes in injured peripheral nerves facilitates development of neuropathic pain via macrophage stimulation. Proc Natl Acad Sci USA. 2009;106:13076-13081.

88. Selim K, Sinan C, Suleyman S, Mete O, Mustafa S, Haluk K. Effects of central and peripheral administration of leptin on pain threshold in rats and mice. Neuroendocrinology Lett. 2003;24:193-196.

89. Dunbar JC, Lu H. Leptin-induced increase in sympathetic nervous and cardiovascular tone is mediated by proopiomelanocortin (POMC) products. Brain Res Bull. 1999;50:215-221.

90. Rene F, Muller A, Jover E, Kieffer B, Koch B, Loeffler JP. Melanocortin receptors and delta-opioid receptor mediateopposite signalling actions of POMC derived peptides in CATH cells. European Journal of Neuroscience. 1998;10(5):1885-1894.

91. Vrinten DH, Kalkman CJ, Adan RA, Gispen WH. Neuropathic pain: a possible role for the melanocortin system? European Journal of Pharmacology. 2001; 429:61-69.

92. Yinghong T, Shuxing W, Yuxin M, Grewo L, Hyangin K, Jianren M. Leptin enhances NMDA-induced spinal excitation in rats: A functional link between adipocytokine and neuropathic pain. Journal of Pain. 2011;152:1263–1271.

93. D’Mello R, Dickenson AH. Spinal cord mechanisms of pain. Br J Anaesth. 2008;101:8-16.

94. Doubell TP, Mannion RJ, Woolf CJ. The dorsal horn: state-dependent sensory processing, plasticity and the generation of pain. In: Wall PD, Melzack R, editors. Textbook of pain. Fourth edition. London: Churchill Livingstone. 1999. p. 165-181.

95. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg. 2003;97:1108-1116.

96. Dubner R. Neuronal plasticity and pain following peripheral tissue inflammation or nerve injury. In: Bond M, Charlton E, Woolf CJ, editors. Pain research and clinical management. Proc. Vth World Congress on Pain, vol.5. Amsterdam: Elsevier; 1991. p. 263-276.

97. Mao J, Price DD, Hayes RL, Lu J, Mayer DJ. Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral neuropathy. Brain Res. 1992;598:271-278.

98. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet. 1999;353:1959–1964.

99. Fisher K, Coderre TJ, Hagen NA. Targeting N-methyl-D-aspartate receptor for chronic pain management: preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage. 2000;20:358-373.

100. Hewitt DJ. The use of NMDA-receptor antagonists in the treatment of chronic pain. Clin J Pain 2000;16:S73-S79.

101. Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F et al. Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab. 1996; 81: 3424-3427.

102. Hickey MS, Israel RG, Gardiner SN, Considine RV, McCammon MR, Tyndall GL et al. Gender differences in serum leptin levels in humans. Biochem Mol Med. 1996;59:1-6.

103. Kennedy A, Gettys TW, Watson P, Wallace P, Ganaway E, Pan Q et al. The metabolic significance of leptin in humans: gender-based differences in relationship to adiposity, insulin sensitivity, and energy expenditure. J Clin Endocrinol Metab. 1997;82:1293-1300.

104. Bhasin S, Storer TW, Berman N, Yarasheski KE, Clevenger B, Phillips J et al. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab. 1997;82 (2):407-413.

105. Arslanian S, Suprasongsin C. Testosterone treatment in adolescents with delayed puberty: changes in body composition, protein, fat, and glucose metabolism. J Clin Endocrinol Metab. 1997;82:3213-3220.

106. Karim R, Stanczyk FZ, Brinton RD, Rettberg J, Hodis HN, Mack WJ. Association of endogenous sex hormones with adipokines and ghrelin in postmenopausal women. J Clin Endocrinol Metab. 2015; 100(2): 508-515.

107. Considine RV, Sinha MK, Heiman ML, Kriauciunas, Stephens TW, Nyce MR et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England Journal of Medicine. 1996; 334: 292-295.

108. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Yet al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Medicine. 1995;1:1155-1161.

109. Vettor R, Vicennati V, Gambineri A, Pagano C, Calzoni F, Pasquali R. Leptin and the hypothalamic-pituitary-adrenal axis activity in women with different obesity phenotypes. International Journal of Obesity. 1997;21:708-711.

110. Ramachandran A, Snehalatha C, Vijay V, Satyavani K, Latha E, Haffner S. Plasma leptin in non-diabetic Asian Indians: association with abdominal adiposity. Diabetic Medicine. 1997;14:937-941.

111. Wauters M, Mertens I, Considine R, Leeuw ID, Van Gaal L. Are leptin levels dependent on body fat distribution in obese men and women? Eating and Weight Disorders. 1998;3:124-130.

112. Hube F, Lietz U, Igel M, Jensen PB, Tornqvist H, Joost HG et al. Difference in leptin mRNA levels between omental and subcutaneous abdominal adipose tissue from obese humans. Hormone and Metabolic Research. 1996;28:690-693.

113. Montague CT, Prins JB, Sanders L, Digby JE, O’Rahilly S. Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Diabetes. 1997; 46(3): 342-347.

114. Lefebvre AM, Laville M, Vega N, Riou JP, van Gaal L, Auwerx J et al. Depotspecific differences in adipose tissue gene expression in lean and obese subjects. Diabetes. 1998;47:98-103.

115. Casabiell X, Pineiro V, Peino R, Lage M, Camina J, Gallego R et al. Gender differences in both spontaneous and stimulated leptin secretion by human omental adipose tissue in vitro: dexamethasone and estradiol stimulate leptin release in women, but not in men. Journal of Clinical Endocrinology and Metabolism. 1998;83:2149-2155.

116. Schwartz M, Peskind E, Raskind M, Boyko EJ, Porte D. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nature Medicine. 1996;2:589-593.

117. Sivan E, Whittaker P, Sinha D, Homko CJ, Lin M, Reece EA et al. Leptin in human pregnancy: the relationship with gestational hormones. American Journal of Obstetrics and Gynecology. 1998; 179: 1128-1132.

118. Kristensen K, Pedersen SB, Richelsen B. Regulation of leptin by steroid hormones in rat adipose tissue. Biochemical and Biophysical Research Communications. 1999;259:624-630.

119. Lahlou N, Landais P, De Boissieu D, Bougneres PF. Circulating leptin in normal children and during the dynamic phase of juvenile obesity, relation to body fatness, energy metabolism, caloric intake, and sexual dimorphism. Diabetes. 1997; 46: 989-993.

120. Shimizu H, Shimomura Y, Nakanishi Y, Futawatari T, Ohtani K, Sato N et al. Estrogen increases in vivo leptin production in ratsand human subjects. Journal of Endocrinology. 1997;154:285-292.

121. Chebab FF, Mounzih K, Lu R, Lim ME. Early onset of reproductive function in normal female mice treated with leptin. Science. 1997; 275: 88-90.

122. Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet. 1996;12:318-320.

123. Wabitsch M, Blum WF, Muche R, Braun M, Hube F, Rascher W et al. Contribution of androgens to the gender difference in leptin production in obese children and adolescents. Journal of Clinical Investigation. 1997;100(4):808-813.

124. Wu-Peng S, Rosenbaum M, Nicolson M, Chua SC, Leibel RL. Effects of exogenous gonadal steroids on leptin homeostasis in rats. Obesity Research. 1999;7:586-592.

125. Hislop M, Ratanjee B, Soule S, Marais A. Effects of anabolic androgenic steroid use or gonadal testosterone suppression on serum leptin concentration in men. European Journal of Endocrinology. 1999;141:40-46.

126. Palmert MR, Radovick S, Boepple PA. The impact of reversible gonadal sex steroid suppression on serum leptin concentrations in children with central precocious puberty. Journal of Clinical Endocrinology and Metabolism. 1998;83:1091-1096.

127. Behre HM, Simoni M, Nieschlag E. Strong association between serum levels of leptin and testosterone in men. Clinical Endocrinology. 1997;47:237-240.

128. Jockenhovel F, Blum WF, Vogel E, Englaro P, Muller-Wieland D, Reinwein D et al. Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men. Journal of Clinical Endocrinology and Metabolism. 1997;82:2510-2513.

129. Garcia-Mayor RV, Andrade MA, Rios M, Lage M, Dieguez C, Casanueva FF. Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary-gonadal hormones and pubertal stage. Journal of Clinical Endocrinology and Metabolism. 1997; 82: 2849-2855.

130. Haffner SM, Miettinen H, Karhapa EE, MykkaEnen L, Laakso M. Leptin concentrations, sex hormones, and cortisol in non-diabetic men. Journal of Clinical Endocrinology and Metabolism. 1997; 82: 1807-1809.

131. Janssen J, Huizinga N, Stolk R, Grobbee D, Pols H, de Jong FH et al. The acute effect of dexamethasone on plasma leptin concentrations and the relationships between fasting leptin, the IGF-I/IGF-BP system, dehydro-epiandrosterone, androstenedione and testosterone in an elderly population. Clinical Endocrinology. 1998; 48: 621-626.

132. Grosman H, Fabre B, Lopez M, Scroticati C, Lopez Silva M, Mesch V et al. Complex relationship between sex hormones, insulin resistance and leptin in men with and without prostatic disease. Aging Male. 2016;19(1):40-45.

Received on 14.02.2020 Modified on 05.04.2020

Research J. Pharm. and Tech. 2020; 13(12):6284-6290.

DOI: 10.5958/0974-360X.2020.01093.8