Take WHAT to Sleep?

The Effects of Sodi­um Oxy­bate on Clin­i­cal Symp­toms and Sleep Pat­terns in Patients With Fibromyalgia

From Jour­nal of Rheumatology
May 2003 (Vol­ume 30, Num­ber 5)

The Effects of Sodi­um Oxy­bate on Clin­i­cal Symp­toms and Sleep Pat­terns in Patients With Fibromyalgia
Scharf MB, Bau­mann M, Berkowitz DV
Jour­nal of Rheuma­tol­ogy. 2003;30(5):1070–1074

Scharf and col­leagues report a dou­ble-blind, ran­dom­ized, place­bo-con­trolled cross-over tri­al of sodi­um oxy­bate in patients with fibromyal­gia (FM). They eval­u­at­ed the effects of sodi­um oxy­bate, a com­mer­cial form of gam­ma-hydrox­y­bu­tyrate (GHB), on the sub­jec­tive symp­toms of pain, fatigue, and sleep qual­i­ty and the objec­tive polysomno­graph­ic sleep vari­ables of alpha intru­sion, slow-wave (stage 3/4) sleep, and sleep effi­cien­cy in patients with FM. They stud­ied 24 female patients of which 18 com­plet­ed the tri­al. The patients who dropped out were in the active med­ica­tion por­tion of the study, and none of the side effects were con­sid­ered seri­ous events (tran­sient episodes of headache, anx­i­ety attack, or paresthesia).

In the inten­tion-to-treat analy­sis of all patients who entered the pro­to­col, ten­der-point index was decreased from base­line by 8.5, com­pared with an increase of 0.4 for the place­bo (P = .0079) por­tion of the cross-over tri­al. Sodi­um oxy­bate was asso­ci­at­ed with relief of 29% to 33% of 6 of the 7 pain/fatigue scores (over­all pain, pain at rest, pain dur­ing move­ment, end-of-day fatigue, over­all fatigue, and morn­ing fatigue), com­pared with relief of 6% to 10% with place­bo (P .005). Slow-wave (stage 3/4) sleep was sig­nif­i­cant­ly increased while alpha intru­sion, sleep laten­cy, and rapid eye move­ment (REM) sleep were sig­nif­i­cant­ly decreased com­pared with place­bo (P .005). Two of the 5 sub­jec­tive sleep-relat­ed vari­ables were sig­nif­i­cant­ly dif­fer­ent from place­bo: morn­ing alert­ness (improved by 18% with sodi­um oxy­bate, com­pared with 2% for place­bo; P = .0033) and qual­i­ty of sleep (improved by 33% and 10%, respec­tive­ly; P = .0003). The inves­ti­ga­tors con­clude that sodi­um oxy­bate effec­tive­ly reduced the symp­toms of pain and fatigue in patients with FM, dra­mat­i­cal­ly reduced the sleep abnor­mal­i­ties of alpha intru­sion, and decreased slow-wave sleep asso­ci­at­ed with the char­ac­ter­is­tic non­restora­tive sleep. This study is impor­tant for rheuma­tol­o­gists, because fatigue and fibromyal­gia are com­mon prob­lems in our patients and a new effec­tive class of drugs may improve func­tion­al out­come in FM patients. FM is asso­ci­at­ed with alpha intru­sion dur­ing sleep[1] and low growth hor­mone secretion.[2] Mold­of­sky and cowork­ers have demon­strat­ed that alpha intru­sion on the elec­troen­cephalo­gram (EEG) is a nor­mal part of wake­ful­ness; how­ev­er, when it occurs too fre­quent­ly in sleep, it is accom­pa­nied by day­time com­plaints of mus­cu­loskele­tal pain, fatigue, and altered mood.[2,3] Although the mech­a­nisms of sleep induc­tion main­te­nance in nor­mal indi­vid­u­als are poor­ly understood,[4] they are even more com­plex and mul­ti­fac­to­r­i­al in patients with FM[2] and in patients with inflam­ma­to­ry process­es asso­ci­at­ed with proin­flam­ma­to­ry cytokines such as tumor necro­sis factor.[5] In nor­mal sub­jects, patients with FM or inflam­ma­to­ry con­di­tions, and ani­mal mod­els, evi­dence for an increas­ing­ly impor­tant role for GHB has been accumulating.[6,7] GHB is a nat­u­ral­ly occur­ring metabo­lite of the human ner­vous sys­tem, with the high­est con­cen­tra­tion in the hypo­thal­a­mus and basal gan­glia. A com­mer­cial form of GHB has been devel­oped as sodi­um oxy­bate. In healthy human vol­un­teers, sodi­um oxy­bate has been shown to pro­mote a nor­mal sequence of non-REM and REM sleep for 2 to 3 hours. How­ev­er, it is also impor­tant to rec­og­nize that GHB has gained wide recog­ni­tion in the pop­u­lar press as a “recre­ation­al drug” used for date rape[8,9] as it is taste­less and cre­ates a sense of amne­sia when tak­en with alco­hol. Thus, GHB is both a ther­a­peu­tic agent and a recre­ation­al drug. It has seda­tive, anx­i­olyt­ic, and euphor­ic effects. These effects are believed to be due to GHB-induced poten­ti­a­tion of cere­bral gam­ma-aminobu­tyric acid-ergic and dopamin­er­gic activ­i­ties, and recent stud­ies sug­gest the sero­ton­er­gic sys­tem might also be involved.[10] As the sero­ton­er­gic sys­tem may be involved in the reg­u­la­tion of sleep, mood, and anx­i­ety, the stim­u­la­tion of this sys­tem may be involved in cer­tain neu­rophar­ma­co­log­ic events induced by GHB administration.[10] The biol­o­gy of GHB may shed light on the impor­tant abnor­mal­i­ty in sleep and the asso­ci­at­ed hypo­thal­a­m­ic diur­nal vari­a­tions found in FM.[2,11] The poten­tial impor­tance of the study by Sharf and cowork­ers is that no med­ica­tion has pre­vi­ous­ly been shown to improve the EEG sleep arousal dis­or­ders that include pha­sic (alpha-delta), ton­ic alpha non-REM sleep dis­or­ders, or the peri­od­ic alpha cycling alter­nat­ing pat­tern disorder.[12] Tra­di­tion­al hyp­not­ic agents, while help­ful in ini­ti­at­ing and main­tain­ing sleep and reduc­ing day­time tired­ness, do not pro­vide restora­tive sleep or reduce pain. Tri­cyclic drugs, such as amitripty­line and cycloben­za­prine, may pro­vide long-term ben­e­fit for improv­ing sleep but may not have a con­tin­u­ing ben­e­fit beyond 1 month for reduc­ing pain. The basic bal­ance between sleep and wake­ful­ness has been an area of active inter­est in neu­ro­chem­istry in recent years. There have been sig­nif­i­cant advances in under­stand­ing the mol­e­c­u­lar biol­o­gy involved, large­ly based on stud­ies of patients with nar­colep­sy and cat­a­plexy. One emerg­ing area of impor­tance is the neu­ro-hor­mone hypocre­tin (orex­in), whose defi­cien­cy ( 40 pg/mL) is high­ly asso­ci­at­ed with nar­colep­sy and cat­a­plexy (89.5%).[13] In ani­mal mod­els of nar­colep­sy, the absence of hypo­thal­a­m­ic orex­in (hypocre­tin) neu­ropep­tides leads to inabil­i­ty to main­tain wake­ful­ness and intru­sion of REM sleep into wakefulness.[14] Absence of oxyrexen‑2 recep­tor elim­i­nates orex­in-evoked exci­ta­tion of his­t­a­min­er­gic neu­rons in the hypo­thal­a­mus, which gate non-REM sleep onset. In sum­ma­ry, the arti­cle by Scharf and col­leagues demon­strates that sodi­um oxy­bate improves func­tion­al sta­tus in fibromyal­gia patients. This ben­e­fit may result from a sig­nif­i­cant reduc­tion in the sleep abnor­mal­i­ties (alpha intru­sion and dimin­ished slow wave sleep) asso­ci­at­ed with the non­restora­tive sleep that is a crit­i­cal fea­ture of FM. Accord­ing to the authors, no oth­er com­pound has been report­ed to reduce the alpha sleep abnor­mal­i­ty. Although this abnor­mal­i­ty is not spe­cif­ic to FM and its pres­ence has not been dis­tin­guished as a cause or effect in FM, reduc­ing alpha intru­sion appears to cor­re­late with clin­i­cal improve­ment. Ref­er­ences Roizen­blatt S, Mold­of­sky H, Bened­i­to-Sil­va AA, Tufik S. Alpha sleep char­ac­ter­is­tics in fibromyal­gia. Arthri­tis Rheum. 2001;44:222–230. Mold­of­sky HK. Dis­or­dered sleep in fibromyal­gia and relat­ed myofas­cial facial pain con­di­tions. Dent Clin North Am. 2001;45:701–713. Mold­of­sky H, Lue FA, Sha­hal B, Jiang CG, Gor­czyn­s­ki RM. Diur­nal sleep­/wake-relat­ed immune func­tions dur­ing the men­stru­al cycle of healthy young women. J Sleep Res. 1995;4:150–159. Willie JT, Chemel­li RM, Sin­ton CM, Yanag­i­sawa M. To eat or to sleep? Orex­in in the reg­u­la­tion of feed­ing and wake­ful­ness. Annu Rev Neu­rosci. 2001;24:429–458. Dick­stein JB, Mold­of­sky H, Hay JB. Brain-blood per­me­abil­i­ty: TNF-alpha pro­motes escape of pro­tein trac­er from CSF to blood. Am J Phys­i­ol Reg­ul Inte­gr Comp Phys­i­ol. 2000;279:R148-R151. Gam­ma hydrox­y­bu­tyrate (Xyrem) for nar­colep­sy. Med Lett Drugs Ther. 2002;44:103–105. Xyrem approved for mus­cle prob­lems in nar­colep­sy. FDA Con­sum. 2002;36:7. Tel­li­er PP. Club drugs: is it all ecsta­sy? Pedi­atr Ann. 2002;31:550–556. Smal­l­ey S. The per­fect crime. Newsweek. Feb­ru­ary 3, 2003:141:52. Gob­aille S, Schleef C, Hech­ler V, Viry S, Aunis D, Maitre M. Gam­ma-hydrox­y­bu­tyrate increas­es tryp­to­phan avail­abil­i­ty and poten­ti­ates sero­tonin turnover in rat brain. Life Sci. 2002;70:2101–2112. Scharf MB, Hauck M, Stover R, McDan­nold M, Berkowitz D. Effect of gam­ma-hydrox­y­bu­tyrate on pain, fatigue, and the alpha sleep anom­aly in patients with fibromyal­gia. Pre­lim­i­nary report. J Rheuma­tol. 1998;25:1986–1990. Brooks S, Black J. Nov­el ther­a­pies for nar­colep­sy. Expert Opin Inves­tig Drugs. 2002;11:1821–1827. Krahn LE, Pankratz VS, Oliv­er L, Boeve BF, Sil­ber MH. Hypocre­tin (orex­in) lev­els in cere­brospinal flu­id of patients with nar­colep­sy: rela­tion­ship to cat­a­plexy and HLA DQB1*0602 sta­tus. Sleep. 2002;25:733–736. Willie JT, Chemel­li RM, Sin­ton CM, et al. Dis­tinct nar­colep­sy syn­dromes in Orex­in receptor‑2 and Orex­in null mice: mol­e­c­u­lar genet­ic dis­sec­tion of Non-REM and REM sleep reg­u­la­to­ry process­es. Neu­ron. 2003;38:715–730. Abstract