the notion that vns therapy could be a viable adjunctive treatment option for patients with refractory fms is based on the encouraging results of pre - clinical and clinical research studies suggesting that vns therapy may target cns processes involved in pain transmission at both spinal and supraspinal levels and could thus have a beneficial effect on pain associated with fms . vns therapy is generally well tolerated by most patients with epilepsy and depression and is rarely the cause for vns discontinuation and explantation . reported side effects are either associated with surgery and / or stimulation on - periods . the most common surgery - related events are infections . the most common side effects during actual stimulation can include voice alteration , hoarseness , cough , paresthesia , headache , throat pain , nausea , and dyspnea . in fact , in studies of vns for epilepsy the following side effects listed were the only ones occurring in more than 5 % of the study participants only during actual stimulation ( intermittently ), improved over time , and could be alleviated or minimized by changing the stimulation parameters : voice alteration ( 50 %), increased coughing ( 41 %), numbness / tingling ( 28 %), sore throat ( 27 %), nausea ( 19 %), shortness of breath ( 18 %) and indigestion ( 12 %) 21 . the manufacturer of the device , cyberonics , inc ., followed 253 refractory epilepsy patients up to 3 years after implantation . all patients received stimulation according to a standard epilepsy vns stimulation protocol . all of the reported stimulation - related side effects diminished over time ; only 7 . 8 % and 4 . 5 % of patient &# 39 ; s still reported hoarseness and headache , respectively , after two years . after three years , shortness of breath was the most common stimulation related side effect , reported by 3 . 8 % of the 253 patients followed . severe adverse events were limited to respiratory difficulties ( n = 3 ) and severe hoarseness ( n = 3 ). median seizure decreases of 31 . 1 %, 40 . 7 %, and 40 . 4 % were reported for one , two , and three - year follow - ups , respectively . thus , even though mild to moderate side effects may occur due to stimulation , the benefits of the treatment over time were considerable . the safety profile for patients with treatment resistant depression is similar to that seen in epilepsy . vns has been approved in the us for clinical use in treatment resistant epilepsy and in canada and europe also for treatment - resistant depression . at its most recent meeting on jun . 15 , 2004 , the fda &# 39 ; s center for devices and radiological health advisory committee , recommended vns therapy for approval as an adjunctive treatment for depression in the us . vns therapy ™ system is manufactured by cyberonics , inc ., houston , tex . the system consists of the implantable , multi - programmable vns therapy model 102 bipolar pulse generator , the model 302 vns therapy bipolar leads , and the external programming system used to set and change stimulation settings as well as to perform system diagnostics . the pulse generator is housed in a hermetically sealed titanium case and will deliver electrical signals to the vagus nerve powered by a single battery . electrical signals are transmitted from the pulse generator to the vagus nerve via the bipolar lead . the external programming system includes the model 201 programming wand , the model 250 software , and a compatible laptop computer . together these three components provide communication with the pulse generator , so called telemetry . telemetry allows for non - invasive programming , functional assessments ( device diagnostics ), device interrogation , and data retrieval . a system of multiple checks verifies the integrity of communications ; each parameter is programmed and verified individually . magnets for patient use are also provided as part of the vns therapy system . they can either be worn on the patient &# 39 ; s watchband ( watch - style ) or belt ( pager - style ) and can be placed over the pulse generator to activate stimulation or to inhibit stimulation . normal programmed stimulation resumes when the magnet is removed . all patients will be trained in the use of the magnet and will practice the use of the magnet as part of their first programming visit . the implantable vns therapy system has been reliable and safe when used in accordance with its labeling . nerve histology collected from two patients stimulated for more than one year indicates that no significant nerve damage occurs over time from normal vagus nerve stimulation . a wide range of animal studies indicates that stimulation at a frequency & lt ; 50 hz at duty cycles of less than 50 % should not cause nerve damage . additionally , continuous stimulation at lower frequencies ( 10 to 20 hz ) should not cause nerve damage and did not cause nerve damage in two patients treated in an epilepsy clinical study who inadvertently received continuous stimulation for two weeks ( pmaa , 1994 ). excessive stimulation at a combination of high frequency (& gt ; 50 hz ) and an excess duty cycle ( greater than 50 %) has resulted in degenerative nerve damage in laboratory animals . fibromyalgia ( fm ) is a potentially disabling chronic pain disorder characterized by 4 - quadrant plus axial pain of at least 3 months duration and at least 11 of 18 tender points . vagus nerve stimulation ( vns ) has been shown to be safe , tolerable , and efficacious for patients with treatment - resistant epilepsy and depression . in both patient groups , stimulation of the left vagus nerve has been reported to reduce pain perception . a phase i trial to evaluate the tolerability , safety and efficacy of vns implantation and stimulation in patients with fms refractory to conventional pharmacological treatment was carried out . patients were 21 to 55 years of age with at least average overall intellectual function and all were physician - diagnosed with fms for at least 2 years . in order to qualify for entry , potential study participants had to report widespread pain — i . e ., median scores of at least 5 — on a watch - type electronic diary ( minimitter ) that polled them about their pain five times a day on a 0 to 10 severity scale over 9 days . individuals were excluded from participation if they were in litigation at time of enrollment , reported the onset of fm following physical trauma , or had psychotic depression , bipolar disorder , psychotic disorders , or substance abuse / dependence within 10 years as determined by psychiatric diagnostic interview . additional exclusion factors included use of antipsychotic drugs within 3 months of enrollment , use of any non - pharmacological treatment for fms within 2 months of enrollment , history of heart disease , a pulmonary condition resulting in an asa score of greater than iii , or a unilateral or bilateral vagotomy . subsequent to recruitment into the study , participants signed a screening consent to allow the study team to gather additional information for final study inclusion for implantation . the diagnosis of fms was confirmed on two center visits by history ( patient reported having pain in all 4 bodily quadrants plus having axial pain in chest or neck — denoted as 4 + a in table 1 ) and physical examination ( palpation at each of the 18 tender points with 4 kg of force producing tenderness of 3 or greater on a 0 to 10 likert pain scale where 0 was no pain , 5 moderate pain and 10 worst pain possible ). once all information was obtained under the screening protocol , fms patients signed an enrollment consent . on average about 3 months after signing the enrollment consent , study participants were implanted with the vns device . most of this time period was utilized for pre - op testing , scheduling surgery , and other activities related to the startup of the individual trial . during the baseline period , the study participant came to the study center for 2 scheduled visits to obtain baseline measures . implantation of the device was followed by a 2 - week post - surgery recovery period , a 2 - week ramp - up / stimulation adjustment period , and a 12 week period of fixed stimulation treatment , referred to as “ acute study .” after completion of the acute study , participants were able to elect to be enrolled in the follow up study with study visits at 6 , 9 , and 12 months post implantation . patients were assessed approximately every 2 weeks after surgery until the end of the acute study phase 4 months later to assess safety , patient tolerance of vns and to do psycho - physical heat pain testing where participants were randomly presented 7 stimuli ranging from 43 ° c . to 49 ° c . in one - degree increments on 2 random trials for a total of 14 stimulus presentations . in addition , patients wore a watch - type electronic diary for a period of 9 days before surgery and before the end of the acute study phase ; the device queried them about their immediate pain level on a 0 to 10 likert scale five times a day . the treatment study of fibromyalgia used the model 102 vns therapy ™ system ( cyberonics , inc ., houston , tex .). following surgical implantation of the device into eligible participants and a 2 - week recovery period , stimulation ( 30 sec on , 5 min off duty cycle , 20 hz , pw = 250 usec ) was increased to as much as 2 ma over a 2 - week adjustment period and maintained during a 12 - week acute study period . the primary efficacy endpoints evaluated global impression of change and changes in ratings of pain intensity and ratings of physical function ( sf - 36 ). adverse events related to implantation and stimulation were recorded . table 2 provides a summary of the fms status of each participant on baseline and on each of the follow up evaluations . the diagnosis of fms requires 4 quadrant plus axial pain as well as at least 11 of 18 tender points . by the end of the acute study phase after 3 . 5 months of vns , 4 of the 12 patients fulfilled neither of these criteria , one no longer fulfilled the tender point criterion and one the widespread pain criterion . ten patients were followed out to 6 months : 5 no longer fulfilled both criteria and 3 no longer fulfilled the tender point criterion — leaving just 3 of 10 with formal criteria for fms . efforts to date have not suggested unusual safety or tolerability issues when implanting a vns system in patients with fm . this result , coupled with assessments of efficacy that are consistent with beneficial effects on pain intensity and physical function , encourage larger - scale evaluations of vns in the treatment of fm . although a best mode of practicing the invention has been described herein with reference to certain preferred embodiments and methods of treating fms , it will be understood by those skilled in the field from a consideration of the foregoing disclosure , that variations and modifications of the described embodiments and methods may be made without departing from the spirit and scope of the invention . accordingly , it is intended that the invention shall be limited only to the extent required by the appended claims and the rules and principles of applicable law .
this invention relates to the use of vagus nerve stimulation for the treatment of fibromyalgia which comprises applying a therapeutic stimulation signal from a stimulus generator , when activated , to at least some of plural electrodes implanted in stimulating relation of the patient &# 39 ; s vagus nerve and activating the stimulus generator to generate the therapeutic stimulation signal to alleviate the pain under treatment .