Fibromyalgia, also called fibromyalgia syndrome (FMS), is a long-term condition that causes pain  all over the body.

Symptoms of fibromyalgia:

As well as widespread pain, people with FMS may have

- Increased sensitivity of pain  

- Fatigue  

- Muscle stiffness

- Problems with mental processes (known as fibro-fog), such as problems with memory and concentration.

This is the case of 63 years old female patient who presented to the emergency department for acute  onset of severe headache, undocumented fever and blurry vision. Her pain started on the day of  presentation; it was described as debilitating , severe in intensity, and associated with left sided weakness (but not hemiplegia).

Review of the system revealed a smoker, non-alcoholic lady with a chronic history of irritable bowel  syndrome, treated conservatively. On the physical exam, she looked lethargic and anxious, without loss  of consciousness. She was found to have, in addition to her symptoms, neck stiffness, with positive  Kerning and Brudzinski signs.

The preliminary diagnosis of meningitis was made, and the following investigations were performed  urgently: blood tests, pan cultures, lumbar puncture as well as brain CT scan. However, the results  were surprisingly normal. First, lumbar Puncture was clear in aspect, free of any white blood cells,  red blood cells or any pathogenic bacteria, with Glucose=77, Protein=0.44. Second, blood tests showed no signs of infection nor electrolytes disturbances: WBC=12.2 (Neutrophils=70.7%, Lymphocytes=25.5%), Hemoglobin=12.3, Platelets=252, CRP=9.6, Creatinine=0.68 (GFR:92.88), sodium=140, potassium=3.1, Chloride=106, CO2=24, Calcium=8.8, Phosphorus=3.6, Magnesium=1.95. Finally, the CT brain didn’t reveal any signs of meningitis or encephalitis. It didn’t show any signs of ischemia or hemorrhage as well. MRI and angio-MRI brain were also done on the same day and didn’t show any abnormalities. The patient was started on antibiotics and was admitted to the  intensive care unit for close monitoring.

On the next day, the patient was complaining of persistent symptoms which became more generalized,  associated with back stiffness and epigastric pain and tenderness. Liver function tests, cardiac and  pancreatic enzymes were drawn but were all negative; ALT=19, AST=27, GGT=16, Alkaline phosphatase=37, Bilirubin (total/direct) =0.3/0.1, INR=1, PTT=34, Lipase=33, Troponin=14.07. She underwent CT scan abdomino-pelvis which was clear. Further tests were ordered to rule out multisystemic disease such as TSH, Iron, Vitamin B12, Folic acid and ESR but they were within normal limits. Urine culture grew multisensitive Escherichia Coli, blood culture was negative.  Upon further questioning, the patient mentioned a chronic history of anxiety and insomnia. She also reported that her mother was treated with muscle relaxants and antidepressants for chronic body aches.

Consequently, and because patient’s physical exam revealed more than 11 tender points all over the  4 abdominal quadrants and the axial skeleton, and because all the investigations ruled out neurological disease, the diagnosis of fibromyalgia was made, and she was referred to a rheumatologist for  medical and physical therapy.

Figure 1: CT brain- Normal

There are largely neglected aspects of FMS and overlapping syndromes that should be considered  in the future investigations. These patients show abnormalities in a variety of systems like autonomic nervous system, immune system and musculoskeletal system. All these systems are highly  dynamic, and their regulation is very intricate. As a result, not only the systems themselves, but also  their interactions are characterized by a high degree of complexity. Studies to date have examined  one or at best a few components of a single one of these systems and have largely ignored the dynamic processes occurring within the system and the myriad of interacting systems. It would be  highly desirable for future studies to begin to address the complexity of these interactions in patients with FMS and other related syndromes.

1. Bidari, A.; Parsa, B.G.; Ghalehbaghi, B. Challenges in fibromyalgia diagnosis: From meaning of symptoms to fibromyalgia labeling. Korean J. Pain 2018, 31, 147–154.

2. Treede, R.D.; Rief,W.; Barke, A.; Aziz, Q.; Bennett, M.I.; Benoliel, R.; Cohen, M.; Evers, S.; Finnerup, N.B.;  First, M.B.; et al. Chronic pain as a symptom or a disease: The IASP classification of chronic pain for the  international classification of diseases (ICD-11). Pain 2019, 160, 19–27.

3. Wolfe, F.; Schmukler, J.; Jamal, S.; Castrejon, I.; Gibson, K.A.; Srinivasan, S.; Hauser, W.; Pincus, T. Diagnosis  of fibromyalgia: Disagreement between fibromyalgia criteria and clinician-based fibromyalgia diagnosis in a  university clinic. Arthritis Care Res. 2019, 71, 343–351.

4. Eich, W.; Bar, K.J.; Bernateck, M.; Burgmer, M.; Dexl, C.; Petzke, F.; Sommer, C.; Winkelmann, A.; Hauser, W.  Definition, classification, clinical diagnosis and prognosis of fibromyalgia syndrome: Updated guidelines  2017 and overview of systematic review articles. Schmerz 2017, 31, 231–238.

5. Ra_aeli, W.; Malafoglia, V.; Bonci, A.; Tenti, M.; Ilari, S.; Gremigni, P.; Iannuccelli, C.; Gioia, C.; Di Franco, M.;  Mollace, V.; et al. Identification of mor-positive b cell as possible innovative biomarker (mu lympho-marker)  for chronic pain diagnosis in patients with fibromyalgia and osteoarthritis diseases. Int. J. Mol. Sci. 2020,  21, 15.

6. Hackshaw, K.V.; Aykas, D.P.; Sigurdson, G.T.; Plans, M.; Madiai, F.; Yu, L.B.; Bu_ngton, C.A.T.; Giusti, M.M.;  Rodriguez-Saona, L. Metabolic fingerprinting for diagnosis of fibromyalgia and other rheumatologic disorders.  J. Biol. Chem. 2019, 294, 2555–2568.

7. Wolfe, F. Criteria for fibromyalgia? What is fibromyalgia? Limitations to current concepts of fibromyalgia  and fibromyalgia criteria. Clin. Exp. Rheumatol. 2017, 35, S3–S5.

8. Walitt, B.; Nahin, R.L.; Katz, R.S.; Bergman, M.J.; Wolfe, F. The prevalence and characteristics of fibromyalgia  in the 2012 national health interview survey. PLoS ONE 2015, 10, e0138024.

9. Moore, R.A.; Straube, S.; Aldington, D. Pain measures and cut-o_s—No worse than mild pain as a simple,  universal outcome. Anaesthesia 2013, 68, 400–412.

10. Espejo, J.A.; Garcia-Escudero, M.; Oltra, E. Unraveling the molecular determinants of manual  therapy: An approach to integrative therapeutics for the treatment of fibromyalgia and chronic fatigue syndrome/myalgic encephalomyelitis. Int. J. Mol. Sci. 2018, 19, 19.

11. Calandre, E.P.; Rico-Villademoros, F.; Slim, M. An update on pharmacotherapy for the treatment of  fibromyalgia. Expert Opin. Pharmacother. 2015, 16, 1347–1368.

12. Thorpe, J.; Shum, B.; Moore, R.A.; Wi_en, P.J.; Gilron, I. Combination pharmacotherapy for the treatment of  fibromyalgia in adults. Cochrane Database Syst. Rev. 2018, 2.

13. Mease, P.J.; Seymour, K. Fibromyalgia: Should the treatment paradigm be monotherapy or combination pharmacotherapy? Curr. Pain Headache Rep. 2008, 12, 399–405.

14. Kwiatek, R. Treatment of fibromyalgia. Aust. Prescr. 2017, 40, 179–183.

15. Wright, C.L.; Mist, S.D.; Ross, R.L.; Jones, K.D. Duloxetine for the treatment of fibromyalgia. Expert Rev.  Clin. Immunol. 2010, 6, 745–756.

16. Pacher, P.; Batkai, S.; Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy.  Pharmacol. Rev. 2006, 58, 389–462.

17. De Vries, M.; van Rijckevorsel, D.C.M.;Wilder-Smith, O.H.G.; van Goor, H. Dronabinol and chronic pain:  Importance of mechanistic considerations. Expert Opin. Pharmacother. 2014, 15, 1525–1534.  18. Russo, E.B. Clinical endocannabinoid deficiency (CECD)—Can this concept explain therapeutic benefits  of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?  Neuroendocr. Lett. 2004, 25. (Reprinted from Neuroendocrinilogy, 2004, 25, 31–39).

19. Smith, S.C.; Wagner, M.S. Clinical endocannabinoid deficiency (CECD) revisited: Can this concept  explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and  other treatment-resistant conditions? Neuroendocr. Lett. 2014, 35, 198–201.

20. Munro, S.; Thomas, K.L.; Abushaar, M. Molecular characterization of a peripheral receptor for cannabinoids.  Nature 1993, 365, 61–65.

21. Skrabek, R.Q.; Gallmova, L.; Ethans, K.; Perry, D. Nabilone for the treatment of pain in fibromyalgia. J. Pain  2008, 9, 164–173.

22. Walitt, B.; Klose, P.; Fitzcharles, M.A.; Phillips, T.; Hauser,W. Cannabinoids for fibromyalgia. Cochrane Database  Syst. Rev. 2016. Int. J. Mol. Sci. 2020, 21, 7877 20 of 27.

23. Thomas, A.; Baillie, G.L.; Phillips, A.M.; Razdan, R.K.; Ross, R.A.; Pertwee, R.G. Cannabidiol displays  unexpectedly high potency as an antagonist of cb1 and cb2 receptor agonists in vitro. Br. J. Pharmacol. 2007,  150, 613–623.

24. Baumeister, D.; Eich,W.; Lerner, R.; Lutz, B.; Bindila, L.; Tesarz, J. Plasma parameters of the endocannabinoid  system are unaltered in fibromyalgia. Psychother. Psychosom. 2018, 87, 377–379.

25. Kaufmann, I.; Schelling, G.; Eisner, C.; Richter, H.P.; Krauseneck, T.; Vogeser, M.; Hauer, D.; Campolongo, P.;  Chouker, A.; Beyer, A.; et al. Anandamide and neutrophil function in patients with fibromyalgia.  Psychoneuroendocrinology 2008, 33, 676–685.

26. Agarwal, N.; Pacher, P.; Tegeder, I.; Amaya, F.; Constantin, C.E.; Brenner, G.J.; Rubino, T.; Michalski, C.W.;  Marsicano, G.; Monory, K.; et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid  receptors in nociceptors. Nat. Neurosci. 2007, 10, 870–879.

27. Schley, M.; Legler, A.; Skopp, G.; Schmelz, M.; Konrad, C.; Rukwied, R. Delta-9-thc based monotherapy in  fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief. Curr. Med. Res. Opin.  2006, 22, 1269–1276.

28. Fiz, J.; Duran, M.; Capella, D.; Carbonell, J.; Farre, M. Cannabis use in patients with fibromyalgia: E_ect on  symptom relief and health-related quality of life. PLoS ONE 2011, 6, 5.

29. Ware, M.A.; Fitzcharles, M.A.; Joseph, L.; Shir, Y. The e_ects of nabilone on sleep in fibromyalgia: Results of  a randomized controlled trial. Anesth. Analg. 2010, 110, 604–610.