Days lost due to disability of diclofenac-induced adverse drugreactions

Introduction

Diclofenac is one of the most prescribed Non-steroidal anti-inflammatory drugs(NSAID) in India or around the world.1 It isone of the main reason for higher number of Adverse Drug Reactions (ADRs) reportedto diclofenac.2 So we have selected diclofenacas the representative drug to measure the ADRs of traditional NSAIDs. Adverse drugreactions of diclofenac include the reactions on skin, gastrointestinal system,central nervous system, kidney, liver, cardiovascular system, eye, mouth,musculoskeletal system, metabolic, respiratory and others. Cutaneous andgastrointestinal system ADRs are the most commonly occurring ADRs of NSAIDs.3

Cyclooxygynase – II enzyme specific NSAIDs (s-NSAIMs) were introduced to theregulatory market with the evidence of lesser adverse effects when compared to thenon-specific NSAIDs (ns-NSAIDs). But further evidences suggest that the serious ADRslike cardiovascular events were higher with s-NSAIDs than ns-NSAIDs. But still thereis confusion that among ns-NSAIMs which have comparable safety. There are somevariations in the pharmacokinetics which contribute to the differences insafety.4,5 Empirically, diclofenac remain the drug of choice among other NSAIDsin many of the cases.

NSAIDs in general may cause 21-25% of the ADRs.6 ADR is to be considered as an illness and it induces or increasesdisabilities or even causes death. No medicines are free of ADRs. While consideringADR as a disease, the management strategy include prevention, treatment ormitigation.7,8

In 1990, the original Global Burden of Diseases (GBD) study was conducted by theHarvard School of Public Health in collaboration with World Bank and World HealthOrganization (WHO). The study was then repeated in 2002 & 2004.9 The new Global Burden Of Diseases (BOD),Injuries, and Risk Factors Study, was started on 2007 by WHO in collaboration withHarvard University, University of Washington, Johns Hopkins University andUniversity of Queensland.10

Quality Adjusted Life Years (QALY) is used to measure the effectiveness of drugs intreating illness.11

Disability Adjusted Life Years (DALY) is used to quantify the burden of disease orillness.12 The average disability weightof peptic ulcer was counted in GBD 2004 as 0.024 - 0.092.13 DALYs for a disease is calculated as the sum of the Years ofLife Lost (YLL) due to premature mortality in the population and the equivalenthealthy Years Lost due to Disability (YLD).9

The GBD 1990 study used 3% time discounting and non-uniform age weighing. The GBD2002 study used 3% time discounting but uniform age weighing. The GBD 2004 studyused 3% time discounting & non-uniform age weighing.9

Age weighing and time discounting is indented to make more predictability to YLL. Butit was widely criticized for the lack of precision.14 In the global study calculating YLL is more useful and easier thancalculating YLD. YLD calculation is time consuming, it need high level expertise andresources. The incidence rates, severity of the conditions, age of onset, durationof the disease etc are required to calculate YLD.15,16 Many of the times lack ofnational or state wise data on diseases reduce the precision of YLD in globalstudies. Instead YLD is a good measure of a healthcare settings study as the simplerandom sampling methods can be used and limited number of professionals can completethe study in a reasonable time.17

The only difference from the YLD and Days Lost due to Disability (DLD) calculation isthat instead of considering the duration of ADR in years, it is calculated in days.DLD have the advantage over Quality Of Life (QoL) because it also considers theduration and occurrence of the ADR in a particular population. So DLD is moregeneralizable information than QoL. It is also more valuable then DALY whilemeasuring the health outcome due to ADRs except death. Many of the national orglobal studies used DALY. YLD in DALY has limited value in studies involving hugestudy population, but it is highly useful in regional studies involvingcomparatively smaller study population. This could be the one of the first study tofind out DLD of diclofenac induced ADRs.

Objective: Our main objective of the study is to explain the usefulness of DLD inmeasuring ADRs. We had planned to measure the disability happened due to diclofenactablets induced ADRs. DLD can be used to measure the impact of ADRs per 1000population. And prepare the adverse drug profile of diclofenac using DLD.

Methods

DALY has been used to calculate the burden or ill health due to disease or drugrelated injury.15 Considering the localsettings of the study, we had selected YLD, and instead of calculating it for yearswe calculated the disability in days.18

The study was done on the patients attending the community pharmacy at Kasaragoddistrict, South India. Patients (18-65 years old) who were prescribed withdiclofenac tablets without any Fixed Drug Combinations (FDC) were informed to reportany discomfort or illness happening after consuming the drug. Patients reported ADRson their next visit to the pharmacy or they had called to the provided phone numberand reported it. The patients were enquired about the causality of the ADRs. CentralDrugs Standard Control Organization (CDSCO), New Delhi, ADR reporting form was usedalong with Naranjo Scale for causality assessment for documenting ADRs. Possible(1-4), probable (5-8) and definite (more than 9) reactions scored by Naranjo Scaleafter consuming the drug were considered as diclofenac-induced ADRs.19 Doubtful adverse events and the ADRs inducedby other drugs were excluded from the findings.

The formula for calculating DLD with uniform age weight and no time discountingis:

DLD = I x DW x L

I is the number of incidences of disease or injury (ADR)

DW is the disability weight and

L is the average duration of disease or injury in days up to clinical recovery ordeath. (In case of YLD it is years instead of days).

The disability weight value is one minus QoL out of one (QoL scored out of hundredneed to be converted to one before deducting it). Disability Weight (DW) could becalculated in an analogue scale from 0-1. Zero represent complete health and 1represent death or equivalent condition.

The average QoL at the time of ADRs are measured using the Karnofsky ratingscale.20 Data collected was entered tothe Microsoft Excel format and processed to find out the results. The calculationfor DLD was done by using the above mentioned equation without discounting.

Results

About 943 patients received diclofenac tablets in 1000 prescriptions weresuccessfully followed up for possible, probable and definite ADRs. Patients whoreceived diclofenac by a separate prescription at a different occasion in 2010 werecounted as a separate sample. Those who were filling the prescriptions for aparticular indication of the drug were counted as the same sample. There were 561reactions reported among the study population. The ADRs repeated in the same patienton a different occasion in 2010 or different types of ADRs observed in the samepatient were counted separately. There was appreciable response in reporting anyside effect suspected through the phone number provided in the dispensing packet.Average age of study population was 38 years. Among the ADRs reported, 262causalities were males and 299 (53%) causalities were females.

Overall 34 types of ADRs are reported under 12 physiological systems/organs. Mostcommon reactions were on gastrointestinal system (48%), followed by skin (14%),Central Nervous System (10%), renal (7%), cardiovascular (7%), Mouth (5%), Hepatic(3%), Eye (3%), Musculo-Skeletal (MS) (2%), Metabolic (0.6%), Respiratory (0.1%) andOthers including Anaphylaxis (0.4%). Only 5 major groups of ADRs are mentioned inthe table 1. Out of which abdominal pain,cramps or flatulence was the highest in occurrence (107). Followed by 43 withrashes, 42 nausea/vomiting, 37 indigestion, 34 peptic ulcers, and 31 edema. On therare cases, one each of asthma & heart failure, 2 each of Stevens-Johnsonsyndrome & tendinitis, 3 each of jaundice and anaphylaxis reported.

Most of the times diclofenac was prescribed with anti-acid agents like ranitidine oromeprazole, still may patients developed ADRs because of noncompliance.

Eventhough Steven-Johnson syndrom is rare it scored considerable DLD (0.013) becauseof high disabillity weight and longer duration.

There are 107 incidence of abdominal pain and 34 incidence of peptic ulcer. Abdominalpain was the most common ADR of diclofenac. But the most damaging ADR is pepticulcer with or without perforation. It produced 0.078 DLD which is the highest BODamong all ADRs of diclofenac. Followed by rash 0.036 DLD and edema 0.027 DLD. Therewas considerable DLD by acute renal failure (0.012) eventhough only 4 cases arereported.

Discussion

Disability may be caused by a disease, trauma or adverse event while therapy. BOD orDLD gives in extensive information about the severity, duration and occurrence ofthe disease or ADRs. DLD or YLD is a valuable tool for using locally to generatein-depth and generalizable information on disability due to disease or injury.21 YLD and DLD are good tools to measure forlarger population or smaller population studies. But of course if it is a nationwidestudy it needs more time and high resources. The only difference from YLD and DLD isthat the measure is in years and days respectively. The data is interchangeable bysimple one step calculation.

There are considerably large numbers of adverse drug reactions are reported fordiclofenac. Approximately half of them are in the gastrointestinal tract because ofits inhibition on prostaglandins. Still empirically diclofenac is considered as oneof the safest NSAID while comparing the safety profiles of other NSAIDs. This makesdiclofenac a primary choice among NSAIDs.

The data developed through this observational study is highly subjective. There werevery less objective data available. Subjective variation of the research staff andthe study subjects could reduce the precision of results. Geographical variation isanother issue which reduces the generalizability of the results to other areas ofdrug use. QoL is a useful but vague term. There shall be some other physical,mental, social or spiritual factors which could influence the health of the patientsat the time of study. There might be high number of ADRs reported but shall not bethe complete ADR profile of diclofenac. For the common ADRs some underreporting orover reporting shall not be a problem in precision but for the rare and serious ADRseven one or two missed reports would make drastic changes in DLD. Follow up studiesin institutional settings would provide more complete data, but it would take moretime to cover 1000 prescriptions and most of the institutional policies discouragereporting of ADRs. Another potential issue is that the average drugs ininstitutional prescriptions are higher than the community practice. The inpatientsof the hospital also would have other health concerns which make the measurement ofburden of ADRs difficult.

Conclusions

Even if diclofenac is the most chosen NSAID in the region; it has a complex adversedrug profile. The study explains the need of safety monitoring on even the mostprescribed drug of choice. Large numbers of ADRs are reported in the study period.It could be correlated with higher consumption. Its adverse drug profile includesmild, moderate and severe ADRs affecting many organ systems in the body. Still itremains as the more chosen NSAID because of the experiential belief of comparativesafety with other NSAIDs. YLD or DLD are useful measures of calculating disabilitycaused by ADRs in surviving patients. Future studies shall focus on improving theusefulness and precision of DLD in measuring disability cased by ADRs.