a 32-year - old female patient with symptoms of widespread pain , fatigue and sleep problems presented at the outpatient clinic one year ago .
physical examination indicated that range of motion of spine and peripheric joints were not limited and painful .
she had 11 positive tender points ( according to acr 1990 fms classification criteria ) and her wpi and ss scores were 9 and 5 , respectively .
routine laboratory tests ( hemoglobin [ hgb ] : 13.3 g / dl , aspartate aminotransferase [ ast ] : 22 u / l , alanine aminotransferase [ alt ] : 18 u / l , creatinine : 0.49 mg / dl , thyroid stimulating hormone [ tsh ] : 0.707uiu / ml , sedimentation : 14 mm / h and c - reactive protein : 5
pregabalin was prescribed with a dosage of 75 mg / day to be taken at night for the first three days .
the dosage was then increased to 75 mg twice a day for 1 week . during this period ,
the patient complained of drowsiness and dizziness ; however , the effects were not severe enough to require discontinuing the medication .
patient s visual analog scale pain score and fibromyalgia impact questionnaire score decreased from 8 to 4 and from 50 to 33 , respectively , over time .
patient was also asked about drug side effects , such as vertigo , drowsiness , dry mouth , and weight gain . in her last examination , one year after the prescription , the patient complained of mastalgia and tenderness in her breasts without galactoria .
laboratory test results were as follows : serum prolactin ( prl ) : 54.2 ng / ml ( 3.226 ) , tsh : 1.45iu / ml , serum b12 vitamin : 223pg / ml , erythrocyte sedimentation rate : 22 mmhg / h , serum dehydroepiandrosterone sulphate ( dhea - s ) : 556 mg / dl , serum follicle stimulating hormone ( fsh ) : 7.44 , serum luteinizing hormone ( lh ) : 11.35
iu / l , serum estradiol : 37 pg / ml , fasting blood sugar : 100 mg / dl , and serum insulin : 4.8iu / ml .
hpl etiology was not observed ; therefore hpl was considered a side effect of pregabalin .
it was explained to the patient that after stopping the medication , the complaints might resolve themselves over time .
however , the patient did not want to wait for her complaints to resolve in time , and so kebergolin 0.5 mg / day for one week was prescribed .
after one week of use , prl value decreased to 2.44 ng / ml and breast tenderness and mastalgia complaints were completely resolved . as patient did not want to use any further medication , an exercise and physical therapy program was scheduled .
these include hormones , immune system , external stressors , psychiatric aspects , and dysfunction of central and autonomic nervous systems .
recent studies suggest that fms is a neurosensitive disorder characterized by abnormal processing of pain .
various neurotransmitters ( i.e. , serotonin , norepinephrine , dopamine , substance p ) seem to be involved in central sensitization . there are various pharmacological treatment recommendations for fsm .
european league against rheumatism ( eular ) primarily advises the use of pregabalin , duloxetine , and amitriptyline .
guidelines suggest pregabalin in first - line treatment [ 4 , 5 ] . in cases of fms ,
voltage - sensitive calcium channels remain open longer , an effect of an increase in the number of alpha 2-delta subunits .
this causes greater glutamate release in presynaptic gap and increase in superficial dorsal root neurons excitability .
pregabalin is a medication that is structurally analogous to gamma - amino butyric acid ( gaba ) .
it is usually prescribed for chronic pain syndromes such as postherpetic neuralgia , diabetic and peripheric neuropathic pain , partial seizures , sleep disorders , anxiety disorders , and fibromyalgia .
pregabalin , an alpha 2 delta ca channel ligand , has analgesic , anxiolytic and anticonvulsive properties .
being a calcium channel antagonist , it decreases the release of many neurotransmitters such as substance p , norepinephrine , and glutamate [ 68 ] .
common adverse effects of pregabalin include dizziness , vertigo , nausea , vomiting , hypotension , headache , hallucinations , fatigue , cognitive impairment , drowsiness , and peripheric edema .
constipation , rhabdomyolysis , hypersensitivity reaction , akathisia , urticaria , and mastalgia are rarely encountered adverse effects and provided as prospectus information . in the present case , hpl , identified as a rare premarketing side effect that has not been reported in the literature , was observed .
the most frequent cause is prl - secreting tumors . before examining for pituitary tumors as part of differential diagnosis , pregnancy , primary hypothyroidism , liver or renal failure , polycystic ovary syndrome , and medication should be considered . in the present case ,
gynecology and endocrinology departments were consulted in order to analyze those etiologic factors . according to results of physical examinations , laboratory tests and mri findings , the patient s hpl was thought to be drug - induced .
medications are the most frequent cause of non - tumoral hpl . in the case of drug - induced hpl ,
prl levels range from 25 to 100 ng / ml , similar to the present patient s prl level [ 11 , 12 ] .
several drugs are reported to cause hpl , such as antipsychotics , antidepressants ( e.g. , tricyclic and tetracyclic selective serotonin reuptake inhibitors [ ssris ] ) , opiates , antihypertensive medications ( verapamil , methyldopa , reserpine ) , gastrointestinal medications ( metoclopramide , domperidone , histamine receptor blockers ) and estrogens .
dopamine ( prolactin inhibiting factor [ pif ] ) is the most important hypothalamic - inhibiting factor of prl .
it binds to the d2 receptor , affecting lactotroph ( unique among endocrine cells in having a high basal secretory activity , and which are located in the anterior pituitary gland ) cell membranes .
this activation causes suppression of the prl gene expression and inhibition of prl exocytosis ; first , inhibition of adenylyl cyclase and inositol phosphate metabolism , then modification / alteration of several potassium and calcium channels .
antipsychotics like phenothiazines ( chlorpromazine - fluphenazine ) , thioxanthenes ( thiothixene ) , and butyrophenones ( haloperidol ) block dopamine and can lead to development of hpl .
in addition , gastrointestinal medications used to increase gastrointestinal motility may cause hpl in the same way , by blocking dopamine receptors .
most evidence suggests that opioid peptides do not directly affect the pituitary gland and stimulate prl release by inhibiting hypothalamic dopamine secretion . among antihypertensive medications ,
kelley et al . , researched the mechanism of this effect of verapamil , a calcium channel blocker .
researchers concluded that verapamil decreases central dopamine generation , perhaps through n - type calcium channels .
several peptides or neurotransmitters , such as serotonin , oestrogens , tachykinins ( substance p , neurokinin a - b and neuropeptide k ) , gonadotropin - releasing hormone associated peptide ( gap ) , opioids ( especially  - endorphins ) , histamine and gaba can also affect the modulation of prl secretion .
gaba , a neurotransmitter secreted mostly in the hypothalamus , has a mostly inhibiting effect .
gaba modulates secretion of pituitary hormones through dopaminergic tone or influence on the anterior pituitary cells .
stimulation of gaba - a and gaba - b receptor decreases prl secretion ; however , nakayama et al . , reported that gaba - c receptor activation led to an increase in prl levels in cultured rat anterior pituitary cells .
pregabalin is an analog of gaba , but it shows no effect on gaba receptors .
activation mechanism is disclosed with calcium channel blocking . though it can not be precisely explained how pregabalin induced hpl in the present case , only the use of pregabalin accounts for its occurrence . in conclusion , this is the first case report demonstrating hpl due to pregabalin usage .
although it has been identified as a premarketing adverse side effect , there is no recent case report in the literature . as it is a very rare side effect , in clinical practice ,
mastalgia is generally not questioned , though the most frequent side effects are routinely questioned .
based on this case report , when pregabalin is used , the authors suggest professionals also inquire about breast tenderness .
 several pharmacological and non - pharmacological modalities have been proposed for the treatment of fibromyalgia syndrome ( fms ) , a common rheumatic disease . 
 pregabalin is suggested as a first - step medication for fms in the newest guidelines . 
 drowsiness , dizziness , and peripheral edema are well - known side effects of pregabalin ; however , mastalgia is rarely seen . 
 presently described is a case of fms in a patient who developed mastalgia and hyperprolactinemia ( hpl ) while taking pregabalin . 
CASE REPORT
DISCUSSION