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Efficacy and side-effect profiles of lactulose,
docusate sodium, and sennosides compared to PEG
in opioid-induced constipation: A systematic review
by Teresa Ruston, Dr. Kathleen Hunter, Dr. Greta Cummings, and
90% in patients with non-cancer pain (Panchal, Muller-Schwefe, & Dr. Adriana Lazarescu
Wurzelmann, 2007), and as high as 95% in patients with cancer pain (Woolery et al., 2008). Since opioids are prescribed for a number of Abstract
pain conditions, including cancer pain, non-cancer pain, and drug Opioid-induced constipation (OIC) is a side effect of opioid therapy management (e.g. methadone) programs, OIC is a prevalent clinical that can affect quality of life, adherence to treatment, and morbidity issue that can affect patients regardless of age, gender, and socioeco- and possibly mortality. nomic status. In addition, since opioids are the standard of care for moderate and severe pain management according to the World Health Objectives: To investigate whether docusate sodium, sennosides, and
Organization's analgesic ladder (World Health Organization, 2011), lactulose have equal efficacy and side effect profiles compared to OIC is a global clinical issue. Finally, the distress associated with OIC PEG in the management of OIC in adults. in affected patients can affect adherence (Panchal et al., 2007), qual- Methods: A systematic review was undertaken. Randomized con-
ity of life (Hjalte, Berggren, Bergendahl, & Hjortsberg, 2010), morbid- trolled trials of adults taking opioids for cancer or non-cancer pain ity (Hawley & Byeon, 2008; Panchal et al., 2007; Woolery et al., 2008), were considered if they met inclusion criteria. and possibly mortality (Hawley & Byeon, 2008).
Conclusions: Statistical pooling was not possible as no studies met Definition
inclusion criteria. Large, well-powered, randomized controlled trials No widely accepted definition of OIC exists. As such, treat- are feasible. Standard definitions of OIC would assist with the exe- ment of this clinical condition lacks robust research and little clin- cution of these studies and contribute to their internal and external ical evidence exists to guide treatment. In contrast, researchers in validity. Further research is strongly encouraged. functional and chronic constipation, and even irritable bowel syn-drome have thoroughly defined their clinical conditions includ- ing both frequency of bowel movements and associated signs and Opioid-induced constipation (OIC) is an unpleasant and ubiquitous symptoms (Lee-Robichaud, Thomas, Morgan, & Nelson, 2010; Rome side effect of opioid therapy. Whereas 2-10% of the general popula- Foundation, 2006). These definitions assist with early recognition, tion suffers from constipation (Caraccia-Economou, 2006); constipa- diagnosis and, ultimately, appropriate treatment. tion associated with opioid use has been reported to be as high as Recognition of the signs and symptoms of OIC have led to a well described, but not all-encompassing condition called opioid bowel dysfunction (OBD). OBD is characterized by hard and dry stools, About the authors
straining, feeling of incomplete evacuation, bloating, abdominal dis- Teresa Ruston, RN, NP, MN, CON(C), Royal Alexandra tention, and increased gastroesophageal reflux (Pappagallo, 2001). Hospital, Alberta Thoracic Oncology Program/Chest However, other signs and symptoms frequently associated with con- Medicine Clinic, Room 4505 Children's Centre, Royal stipation include abdominal pain, nausea, vomiting, loss of appe- Alexandra Hospital, 10240 Kingsway Ave., Edmonton, tite and headaches (Woolery et al., 2008). In addition, OBD does not AB T5H 3V9 describe frequency of stool passage. Therefore, for the purposes of Phone: (780) 735-3972; Fax: (780) 735-3971; Email: this paper, we define OIC as active opioid therapy in addition to at least one of the following: stools that are hard and difficult to pass, straining with bowel movement, and fewer than three stools per Dr. Kathleen Hunter, RN, NP, PhD, GNC(C), NCA, week. Furthermore, associated symptoms such as those described Associate Professor, Nurse Practitioner, Assistant above, may or may not be present. Adjunct Professor, Faculty of Medicine, Division of Geriatric Medicine, Faculty of Nursing Level 3, Edmonton Clinic Health Academy, 11405 87 Ave., Several mechanisms lead to the constipating effects of opioids. University of Alberta, Edmonton, AB T6G 1C9 The cumulative effect is constipation related to hard and dry stools, Phone: (780)492-8941; Fax: (780)492-2551; Email: prolonged transit time, and ineffective gastric emptying. The bind- ing of opioids with gut and central nervous system receptors inhib-its release of acetylcholine from the myenteric plexus, which has an Dr. Greta Cummings, RN, PhD, FCAHS, Professor, inhibitory effect on neuron potential (Camilleri, 2011). A decrease in Faculty of Nursing Level 3, Edmonton Clinic Health peristalsis occurs shortly after opioid administration, and the subse- Academy, 11405 87 Ave., University of Alberta, quent constipating effects are dose-related (Woolery et al., 2008). This Edmonton, AB T6G 1C9 increases transit time of intestinal contents, resulting in increased Phone: (780)492-8703; Fax: (780)492-2551; Email: reabsorption of water and fecal impaction (Pappagallo, 2001). OIC is further complicated by a decrease in intestinal, gastric, biliary, and pancreatic secretions. Finally, an increase in anal sphincter tone, and Dr. Adriana Lazarescu, MD, FRCPC, Assistant a decrease in defecatory reflex interrupts the coordination required Professor, Division of Gastroenterology, 2-30A Zeidler- for effective colonic emptying (Wood & Galligan, 2004).
Ledcor, 130 University Campus, University of Alberta, Edmonton, AB T6G 2X8 Phone: (780)248-1498; Email: Since little evidence exists to guide practice, pharmaco- logic intervention is frequently done on a trial-and-error basis, 236 CONJ • RCSIO Fall/Automne 2013 potentially resulting in negative outcomes. If the patient does not that guided this review was: Do docusate sodium, sennosides, and lac-receive prompt relief, this results in reduced adherence to opioid tulose used in constipation prevention and management of OIC have treatment, decreased quality of life, and increased morbidity and equal efficacy and adverse effect profiles compared to PEG granules in mortality. Patients have reported they would rather suffer pain adults receiving opioid treatment for a variety of conditions?than constipation (Panchal et al., 2007). Accordingly, some would even rather endure pain than continue with opioid treatment (Choi & Billings, 2002). Predictably, patients also report worsening qual- An unpublished protocol was created and reviewed by the authors ity-of-life scores, as constipation and its associated symptoms prior to beginning the systematic review. The protocol ensured that worsen (Hjalte et al., 2010). In addition, compared to non-consti- we would address and report our methodology according to the pated patients, constipated patients receiving opioid therapy for internationally recognized Preferred Reporting Items for Systematic more than six months were more likely to visit their physicians, Reviews and Meta-Analyses (PRISMA) statement (Liberati, Altman, miss work, feel that their performance at work was impaired, and Tetzlaff, Mulrow, Gotzsche, Ioannidis, Clarke, Devereaux, Kleijnen, have symptoms that impaired their ability to undertake activities & Moher, 2009). We also completed an unpublished scoping review of daily living (Annunziata & Bell, 2006). Finally, obstructive consti- as part of preparation, which revealed that little evidence existed. pation causing life-threatening bowel obstruction may require inpa- Therefore, we expected that completed research articles comparing tient treatment or invasive surgery, resulting in lengthy hospital various treatment regimens for OIC would be minimal. To ensure stays (McNicol, Boyce, Schumann, & Carr, 2008; Pappagallo, 2001).
that our search was as extensive as possible, we sought the support Current strategies to manage OIC include non-pharmacologic and of two health science research librarians, one of whom had a spe- pharmacologic means. Non-pharmacologic strategies include exer- cial interest in pharmacy science. With their assistance we kept the cise, increased intake of fibre and fluids, and a regular toilet rou- search terms broad, in order to obtain an inclusive search strategy. tine (Pappagallo, 2001). Typical trial-and-error regimens include use
of sennosides and docusate sodium two to three times per day. If Search strategy
these medications are ineffective, lactulose, polyethylene glycol (PEG)
In September 2012, we conducted a search of the databases granules, oral fleets, enemas, and suppositories are used (Swegle & Cochrane Central Registry of Controlled Trials (CENTRAL), MEDLINE, Logemann, 2006). See Table 1 for the mechanism of action, benefits, CINAHL, EMBASE, International Pharmaceutical Abstracts, Scopus, and side effects of the laxatives investigated in this study.
DARE, Web of Science, Proquest, Grey Matters and Grey Source. We did not restrict the year of publication, as the inclusion of PEG in the search terms would limit studies to when PEG was introduced in the A recent systematic review by Lee-Robichaud, Thomas, Morgan, early 1990s. Language was also not restricted in an attempt to dis- and Nelson (Lee-Robichaud et al., 2010) demonstrated superior clinical cover all articles related to the topic, with the goal of translating rel- efficacy of PEG to lactulose in children and adults with chronic consti- evant articles with support from colleagues or Google TranslateTM pation. Therefore, we wanted to investigate whether or not PEG was where feasible. Moreover, we did not include any restrictions on age. superior to docusate sodium, sennosides, and lactulose in OIC in order An inclusive search would allow us to identify and exclude random- to make evidence-based treatment recommendations. The question ized controlled trials (RCTs) that focused solely on children. The Table 1: Laxatives
Docusate sodium Facilitate the mixing of aqueous and fatty substances (Woolery et al., 2008) (Woolery et al., docusate calcium Poorly absorbed ions or molecules create a Stimulates Electrolyte abnormalities (Woolery et local osmotic gradient within the intestinal peristalsis via lumen (Woolery et al., 2008) increase in pressure Altered bowel flora can cause Peristalsis is stimulated by increase in (Woolery et al., bloating, flatulence, colic, and pressure from reabsorption of fluid and excessive diarrhea (Lee-Robichaud et electrolytes, and decreased gut pH in the colon (Lee-Robichaud et al., 2010) Iso-osmotic Polyethylene Iso-osmotic laxatives are physiologically Makes stools softer inert; they are not absorbed or metabolized and easier to pass Pain, nausea, excessive diarrhea (Lee- (Woolery et al., Robichaud et al., 2010) with electrolytes Opposes water absorption from stool in the large bowel, increasing water content Colytely®); low and volume of the stools (Woolery et al., electrolytes (PEG 3350, Miralax®) Senna (Senokot® Irritate the nerve endings in the colonic Stimulate peristalsis Abdominal discomfort mucosa, stimulating peristalsis. May also (Woolery et al., (cramping), electrolyte imbalances limit water absorption by altering fluid (hypokalemia), (Lee-Robichaud et and electrolyte transportation within the Suitable for patients al., 2010) allergic reactions, and intestinal mucosa (Woolery et al., 2008) intolerant to fibre Melanosis coli (a pigmentation (Lee-Robichaud et disorder of the bowel) has also been reported with senna containing compounds (Woolery et al., 2008) CONJ • RCSIO Fall/Automne 2013 237 keywords and MeSH terms used for MEDLINE are presented in Table did not keep previous conference proceedings. Since the publication of 2. Our research librarians adapted these keywords, so that appropri- studies using PEG for chronic constipation began in 1990, screening ate search terms could be used in the other databases.
was limited to the start date of that year through to September 2012.
Screening other resources
Study selection and data extraction
In order to avoid publication bias, a thorough search of the grey Studies were included if they met the following inclusion crite- literature was done via search engines outlined above. In addition, ria: (i) Study design: RCT. (ii) Patient population: patients 18 years hand searching of reference lists, drug monographs, and conference or older with constipation associated with chronic opioid use—proceedings was done to identify any further studies. Available con- e.g., chronic cancer or non-cancer pain, or substance withdrawal ference proceedings reviewed were: Canadian Association of Nurses (i.e., methadone program); opioid dose must be reported for com-in Oncology, Oncology Nursing Society, American Society of Clinical parative purposes. (iii) Intervention: must compare at least one Oncology (only relevant sections, i.e. we did not review breast can- of—lactulose, docusate sodium, or sennosides—to PEG (PEG must cer, prostate cancer, etc.), International Congress on Palliative Care, be included in all studies), dosing for laxatives must be reported American Gastroenterological Association, and Canadian Association for comparative purposes. (iv) Setting of care: patients may be of Gastroenterology. We also attempted to review the Canadian Society inpatients, outpatients, or palliative care patients. (v) Outcome of Gastroenterological Nurses and Associates, and the Society of measures: primary outcomes measures—efficacy (measures by fre-Gastroenterological Nurses and Associates. However, these associations quency of bowel movements), quality of stool (hard, soft, or loose), secondary outcome measures—side effects, drug interactions, use Table 2: MEDLINE search terms
of additional laxatives, relief of constipation associated symptoms. Two of the reviewers (TR, KH) independently scanned the titles, abstracts, and keywords of records retrieved against inclusion and exclusion criteria to select studies for further assessment. The same two reviewers independently assessed full articles for inclusion. Disagreements were managed by consensus, and a third author was (constipat* or dyschezia or colonic inertia consulted when necessary. Also, the same reviewers independently or f?eces or f?ecal or retention or delayed extracted data regarding details of study population, intervention, bowel movement or obstipation or and outcomes using a standard data extraction form specifically costiveness or irregular* or egest).tw.
adapted for this review. Interrater reliability was not assessed, as no articles fit the inclusion criteria, and only one article is included for discussion purposes. If necessary, two attempts were made to con- tact trial authors to provide missing data of the article included for discussion. Response was received for the article that will be dis- Polyethylene Glycols/ cussed, but the necessary information required to meet full inclu-sion criteria was not available.
(peg or peg granules or laxaday or polyethylene glycol or ethylene glycol or ethylene oxide or PEO or polyethers Had our study found articles for inclusion, two researchers (TR, or movicol or polyethylene glycol 3350 KH) would have independently performed quality assessment using or miralax or glycoLax or GoLYTELY or the Cochrane Collaboration's tool for assessing risk of bias (Liberati glycolax or fortrans or trilyte or colyte).tw.
et al., 2009). This tool was created to examine risk of bias in RCTs. It allows the assessor to search for potential sources of bias, including whether or not the trial performed sequence generation, allocation Dioctyl Sulfosuccinic Acid/ concealment, blinding, completed data, and selective outcome report- (colace or docusate sodium or docusate ing, before giving an overall risk score to the article. Again, any dis- salt* or docusate calcium or sulfosucc* or agreements were resolved by consensus. dioctyl calcium sulfosuccinate or correctol or diocto or docusoft or dok or dos or Statistical methods
ex-lax or sof-lax or gentlax or peri-colace or Although our protocol had planned rigorous statistical analy- sis, pooling of data was not possible, as no articles met the inclusion criteria. Study identification
Figure 1 (PRISMA diagram) (Higgins & Altman, 2008) outlines our (senokot or sennosides or lactulose or electronic searches. We retrieved 2,158 references, 25 of which were disaccharide or generlac or cephulac or selected for full article review. Hand searching did not identify any cholac or constilac or enulose or cilac or further studies, but reference list browsing did identify three arti- heptalac or actilax or duphalac or kristalose cles. None of the articles found in any of the searches met the full inclusion criteria. We have, nevertheless, included one article for dis- cussion purposes only (Freedman, Schwartz, Roby, & Fleisher, 1997). Table 3 describes the details of the included article. Had the authors reported the doses of methadone and PEG, the article would have met full inclusion criteria. We were able to contact one of the origi-nal authors who replied that these data were no longer available. As a research team, we felt that the study was a good example of what type of research is required in the future to address this topic.
238 CONJ • RCSIO Fall/Automne 2013 dose of opioid, dose of laxative, and characteristics of constipation. Statement of principal findings
Constipation should be reported according to an all-encompassing At this time, there are insufficient studies to determine if PEG standard definition, such as our definition of OIC. This is especially is superior to lactulose, docusate sodium, and sennosides for OIC. important because the number of bowel movements per week does There were also insufficient studies to undertake statistical analy- not always indicate whether or not constipation is present (McNicol ses of the available literature.
et al., 2008). In addition, the adoption of a standard definition across studies is in accordance with the Standards for the Reporting of Current context and future research directions
Diagnostic Accuracy (STARD). Through research, these standards More randomized controlled trials are required related to patients improve the precision and completeness of diagnostic accuracy, thus with OIC. Ideally, studies should report certain characteristics to improving internal and external validity (STARD, 2008). allow for comparison among studies including, but not limited to Study design should also allow patients to be on laxative ther- apy for a period of time that would allow analysis of efficacy of treatment and the appearance of potential side effects. To observe Databases: CENTRAL, MEDLINE, CINAHL, EMBASE, International Pharmaceutical
Abstracts, Scopus, DARE, Web of Science, Proquest, Grey Matters and Grey Source short-term side effects, a minimum of three to four weeks of laxa- Meeting Abstracts: CANO, ONS, ASCO, International Congress on Palliative Care,
tive therapy would be ideal. However, assessment of long-term effi- Hand Searching: Reference Lists, Drug Monographs, Conference Proceedings
cacy would likely require several months of treatment. Reporting both laxative and opioid doses would allow for comparison among studies, statistical assessment (such as meta-analysis), and calcula-tion of confounding variables. Ultimately, since opioid medications Combined search results (n=2158) are widely used throughout the world with constipation being one of the most common side effects (Panchal et al., 2007; Pappagallo, Duplicates removed (n=603) 2001), well-powered studies are achievable, and the timeframe required for recruitment and data analysis is feasible. Articles screened by title and abstract (n=1555) Over the last decade, funded research for OIC has had a strong focus on opioid antagonists such as naloxone, alvimopan, and methylnaltrexone. Although this research is important, we call for Excluded (n=1530) Did not meet inclusion criteria (e.g., wrong population, research on lactulose, docusate sodium, sennosides and PEG to gain a wrong laxative therapy, wrong constipation condition) better understanding of the efficacy and side effect profiles of these laxatives, for several reasons. First, lactulose, docusate sodium, sen- Manuscript review and application of inclusion nosides, and PEG are relatively inexpensive and easy for patients to use and adhere to. Clinicians can successfully teach patients how to self-titrate these medications based on the consistency of their stool (Freedman et al., 1997). Second, opioid antagonists are indicated for Did not meet inclusion criteria (e.g., wrong population, use only when response to laxative therapy has not been sufficient. wrong laxative therapy, wrong constipation condition) Arguably, if clinicians had high-quality evidence to guide laxative decision-making in OIC, we may be able to increase laxative response Included studies (n=0) and avoid the need for opioid antagonists. Third, laxative therapy is much more affordable than opioid antagonists. Whereas each injec- Figure 1: PRISMA flow diagram
tion of methylnaltrexone bromide costs patients $35 CAD (and they CANO = Canadian Association of Nurses in Oncology; ONS= Oncology may require two to three injections per week), patients can use once- Nursing Society; ASCO= American Society of Clinical Oncology; AGA= daily dosing of generic brand PEG for $26 CAD per month (Intelliware American Gastroenterological Association; and CAG= Canadian As- Development Inc., 2011). sociation of Gastroenterology Table 3: Details of discussed article
Objective/ Definition of Description of
Interventions and Controls Co-Intervention(s)
Freedman, M., Schwartz, Setting: Outpatients Objective: To study PEG 1st week=control period; no Co-Intervention: Milk of *Lactulose and PEG Side Effects for J., Roby, R., & Fleisher, on a methadone drug with electrolytes in treating interventions *Methadone maintenance Analysis: Weekly resulted in fewer hard maintenance program non-organic constipation in Dose: Not reported for remainder of study stools (hard, soft, stools than placebo and Reported adverse methadone maintenance Non PEG: #1- Placebo; Dose: Route: Not reported, but or loose) reported Tolerance and efficacy patients with constipation 240mL; Route: PO; Timing: PO is most common *Previous use of laxatives significant compared of polyethylene glycol Randomized to all despite the use of lactulose Every night Timing: as needed *>18 years of age differences between 3350/ electrolyte lactulose or PEG solution versus lactulose regimens; used Latin Definition: not reported Co-Intervention: Dulcolax Exclusion: Length of Follow *Increased frequency of Side Effects for PEG: in relieving opiate square assignment Dose: 30 mL; Route: PO; Dose: Not reported *Women if pregnant or loose (diarrheal) stools *Increased induced constipation: A Study described as Timing: Every night Route: Not reported week control period with PEG compared to frequency of loose double-blinded placebo- double blind PEG 3350 WITH ELECTROLYTES Timing: as needed *Patients with elevated TSH, followed by 2 weeks control; no change in Dose: Not reported; Route: history of colonic surgery, on either placebo, electrolytes between with control; but PO; Timing: Every night childhood constipation lactulose, or PEG.
with > 1 purgative procedure/ month, adult requirements for onset constipation , heme co-interventions only in positive stool of unknown *No drug-related etiology, unreliable follow adverse reactions up examination, history of that resulted in withdrawal from study CONJ • RCSIO Fall/Automne 2013 239 Implications for oncology nursing
assist with standardization across studies and improve internal Our systematic review has demonstrated the long-standing lack and external validity. More research is required to assist with evi- of research on OIC. The widespread use of docusate sodium, senno- dence-based treatment of OIC. Studies that examine the efficacy of sides, and lactulose for constipation prevention and management laxatives in OIC are feasible because these medications are inexpen-has been in many hospitals for several years. Nurses should recog- sive, and there are large patient populations in which to examine nize that current treatment of OIC is not evidence-based.
this research question. Large, international, well designed studies Even though lack of sufficient evidence exists for the manage- to investigate this issue are encouraged. More evidence would allow ment of OIC, nurses must use their assessment and evaluation prescribing clinicians, NPs, and frontline nursing staff to provide skills to advocate for the initiation of bowel regimens when symp- better management of this commonly encountered clinical issue. toms of OIC exist. When nurses identify patients starting on opi-oids, they must consider the pathophysiology of OIC, the symptoms with which it presents, and the potential negative sequelae if it This work was supported by the Maurice and Edna Marie Minton does occur. This article outlines why this is particularly import- Endowment Fund for Cancer Nursing Research from the Maurice ant in oncology patients, where many patients require opioids for and Edna Minton Endowment Fund, awarded to Teresa Ruston (nee pain management. Until we have more evidence to support practice, Kerridge). The authors would also like to thank Dr. Katherine Moore, trial and error—where nurses continually assess and evaluate bowel Faculty of Nursing, University of Alberta, for the conceptualization regimens in individual patients—will remain the norm. Ultimately, of this project. Finally, we would also like to thank our two research nurses must encourage and support the future research for this librarians Thane Chambers, MLIS, and Trish Chatterley, BA(Hon), common clinical condition. MLIS, for their many hours of work. OIC is a common side effect of opioid therapy. Insufficient evi- At the time of writing, Teresa Ruston had received a scholarship dence exists to determine the efficacy and side effect profiles of lac- sponsored by Roche from the Alberta Cancer Board Foundation. tulose, docusate sodium, sennosides, and PEG in the treatment of Dr. Kathleen Hunter is co-investigator on a study funded by Astelles OIC. A standard and all-encompassing definition of OIC that reports (unrestricted grant). Dr. Greta Cummings is funded as a Population stools that are hard and difficult to pass, straining with bowel Health Knowledge Investigator by Alberta Heritage Foundation for movement, and fewer than two to three stools per week, and any Health Research. Dr. Adriana Lazarescu is a facilitator with Janssen other associated symptoms is essential. Such a definition would for prucalopride. REFERENCES
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Doping Control Manual 2012 Anti-‐doping Rules Therapeutic Use Exemption (TUE) FIRS Sports Medicine Commission Viale Tiziano 74 00196, Roma, Italy Doping Control Manual TUE December 2009v1 General Information Doping control may occur during any FIRS Events. Athletes, who use medications that are included on the Prohibited List, must fill in the Therapeutic Use Exemption form with their physician. The completed TUE forms must be submitted to the FIRS doping control officer at least 30 days before the event. All documents (TUE form and medical evidence attachments) must be written in English or Spanish. Generic names of medication must be used. Information about Therapeutic Use Exemption (TUE) For substances and methods on the Prohibited List FIRS athletes, like other athletes, may have illnesses or conditions that require them to take particular medications. If the medication that an athlete is required to take to treat an illness or condition happens to fall under the Prohibited List, a Therapeutic Use Exemption will give the athlete the authorization to take the needed medicine. Athletes may apply for a TUE for any treatment involving a substance or method on the Prohibited List. Medical evidence needed to support the diagnosis There needs to be objective medical evidence to confirm the diagnosis and the need for treatment with a prohibited substance. This medical evidence must be supplied by the treating doctor and sent together with the TUE application. Medical evidence shall include complete medical history (for example onset of the disease, family history, triggers, severity, etc.), results of all examinations and laboratory investigations and/or the imaging studies. Required in official FIRS Events All international level athletes defined as athletes in the FIRS Registered Testing and/or players entering in an FIRS World Championship, or a Major Games, who use prohibited substances and/or methods, must fill the TUE Form and submit the Application to the FIRS. FIRS is responsible for accepting applications and granting the certificates. All TUE applications will be reviewed by the FIRS Medical Committee. If approved, the athlete can begin treatment after receiving the authorization notice from the FIRS. In rare cases of an acute life threatening condition retroactive approval will be considered. Reciprocal Approval of TUE FIRS medical commission will accept, by reciprocal arrangement, any TUE issued by a FIRS approved anti-doping organization (ADO) in conformity with the WADA International standards for TUE. ADOs include other International Federations and National anti-doping organizations. Sanction fee for late TUE applications The TUE applications need to be sent to FIRS at least 30 days in advance of the FIRS event. The sanction fee of $50 US may be applied for the late incoming TUE applications. The sanction fee, if applied, shall be paid by the National Federation of the applying athlete.