TABLE
OF CONTENTS
CHAPTER
ONE
1.1
INTRODUCTION
1.2
STATEMENT OF THE PROBLEM
1.3 JUSTIFICATION OF THE STUDY
1.4 STUDY OBJECTIVES
CHAPTER
TWO
METHOD
2.1
SETTING
2.2
STUDY DESIGN
2.3
STUDY POPULATION
2.3.1
PRESCRIBING PATTERN OF PHYSICIANS
2.4
SAMPLE SIZE DETERMINATION
2.5
SAMPLING TECHNIQUE
2.6
DATA COLLECTION
2.7 PRETESTING OF QUESTIONNAIRES
2.8 DATA ANALYSIS
CHAPTER THREE
RESULTS
3.1 RESULTS OF ANALYSIS OF
PRESCRIPTIONS/TREATMENT SHEETS
3.2 RESULTS OF SURVEY OF ILORIN RESIDENTS
3.3.
RESULTS OF SURVEY OF COMMUNITY PHARMACISTS
CHAPTER FOUR
DISCUSSION
CHAPTER FIVE
CONCLUSION
REFERENCES
CHAPTER
ONE
1.1 INTRODUCTION
Nonsteroidal
anti-inflammatory drugs (NSAIDs) are medications used to relieve pain, fever
and inflammation and they include a large group of anti-inflammatory agents
that work by inhibiting the production of prostaglandins. Nonsteroidal
anti-inflammatory drugs (NSAIDs) also represent diverse group of drug with
analgesic property and most frequently prescribed drug globally. They represent
the first choice of
drug with well demonstrated efficiency
for the pain
management primarily musculoskeletal disorder
and osteoarthritis to treat mild to moderate pain. Although its serious
toxicity related to Gastro intestinal tract its choice in this category of its
choice (Gul and Ayub, 2014).
There
is overwhelming evidence linking chronic nonselective NSAID (including aspirin)
use to a variety of Gastrointestinal (GI) tract injuries. Age is a significant risk factor for
NSAID-induced GI events; indeed, patients above 75 years of age carry the
highest risk and are similar in this respect to patients with a history of
peptic ulcer (Beradi and Welage, 2005)
People
desire to take responsibility for their own health care management. Many do so
via self‑medication.
Self‑medication
is defined as the use of over‑the‑counter
(OTC) drugs without consulting a professional health care practitioner. Self‑medication
involves acquiring medication without a prescription, resubmitting an old
prescription to procure medication, sharing medications with others, or
utilizing a medication that is already available in the residence. Several
governmental organizations developed policies to encourage self‑care
for minor illnesses, reclassifying many drugs as nonprescription medications
instead of prescription‑only medications, allowing the drugs to be
administered by patients without a
prescription. (Saeed et al, 2015) and could also be described as
Medication that is
taken on patient's own initiative
or on advice of a pharmacist or lay
person(Neha et al, 2013)
The
terms ‘misuse’ and ‘abuse’ are often used interchangeably, but they have
precise meanings in this context. Misuse is defined as using an OTC product for
a legitimate medical reason but in higher doses or for a longer period than
recommended. Abuse is the nonmedical use of OTC drugs (Gul and Ayub, 2015)
HISTORIC PERSPECTIVE OF NSAIDS
Aspirin
and NSAIDs have a storied history in the treatment of pain and rheumatic
diseases. In the 4th century B.C., Hippocrates detailed the use of powder made
from the bark and leaves of the willow tree (Salixspp.) for headache, pain, and
fever. Ancient Egyptians and Assyrians also used a willow extract to relieve
the pain and erythema of inflamed joints ( Apebum, 2002)
In
1828, Johann Buchner at the University of Munich extracted and purified salicin
from willow, and three decades later, Charles Gerhardt succeeded in
synthesizing a “buffered” form of salicylate to reduce dyspepsia,
acetylsalicylic acid. This synthetic compound, containing no willow
derivatives, was marketed by Felix Hoffmann of the Bayer company in 1899 as
aspirin. The U.S. Food and Drug Administration (FDA) approved aspirin for the
primary and secondary prevention of cardiovascular disease, and the secondary prevention of
stroke and transient ischemic attacks,
in 1988.
Additional
NSAIDs were developed, such as phenylbutazone in 1949, indomethacin in 1963,
and ibuprofen in 1969; however, the mechanism of action of these NSAIDs was
unknown. In 1972, John R. Vane demonstrated that aspirin blocks the synthesis
of a proinflammatory cytokine, prostaglandin E, for which he was granted the
Nobel Prize in 1982 (Vane, 1971)
Prostaglandin
synthase (COX), the enzyme inhibited by aspirin, which converts arachidonic acid to prostaglandins,
was discovered in 1989, and was found to have two isoforms, COX-1 and COX-2;
this discovery paved the way for the
development of COX-2 selective inhibitors, which were hypothesized and later
proven to have reduced GI toxicity.Babberdia,1999, Goldstain, 2001) .The first
COX-2 selective inhibitor, celecoxib
(Celebrex), approved by the FDA in 1998 based upon the results of five clinical trials involving
more than 5000 patients with
degenerative or rheumatoid arthritis, showed comparable analgesia and efficacy
to nonselective NSAIDs and placebo with fewer clinical and endoscopic
gastroduodenal ulcers.(Emery, 1999; silverstainn et al, 2000;Denson et al 1999;
and Bonberdier et al 2000)
Two
other COX-2 selective inhibitors, valdecoxib and rofecoxib, were subsequently
approved; however, in the wake of concerns
of an increased risk of thromboembolic events, and with valdecoxib an
additional risk of Stevens–Johnson syndrome, both were withdrawn from the U.S.
market in 2005(Bresalier et al, 2005; Solomon
et al 2005). Celecoxib remains available for the treatment of pain
associated with degenerative joint disease and rheumatoid arthritis, but as of April 2005
carries a “black box” warning alerting consumers to the increased
cardiovascular risk associated with this medication.
Over
the last few years, professional organizations, including the American College
of Rheumatology, the American Pain Society (Emery et al 1999) , and the European League Against Rheumatism (Silverstein et al, 2000), have
published treatment guidelines to assist clinicians in achieving effective pain
management. Safety is a core concern in all these guidelines, especially for
chronic conditions, such as OA, that require long-term treatment. Hence, there
is a consensus among recommendations that paracetamol (acetaminophen) should be
the first-line analgesic agent due to its favorable side effect and safety
profile, despite several meta-analyses having shown that it is less effective
in pain relief than anti-inflammatory drugs (Scarpignato et al, 2015).
Concerns
have been raised regarding the safety of nonsteroidal antiinflammatory drugs
(NSAIDs), which havebeen linked to increased cardiovascular morbidity. This
association was first established in large clinical trials investigating the
effect of selective cyclooxygenase-2 (COX-2) inhibitors on preventing
gastrointestinal ulcers and gastrointestinal polyps. Later, these results have
been confirmed in several large-scale observational studies(FitzGerald, 2003).
Pharmacists
are usually the custodian of drugs and are charged with the responsibilities of
delivering safe and efficacious medicines to the public (Owusu-Ansah, 2009) .
In developing countries, traders perceive drugs as items of trade. In Nigeria,
a country where the ratio of pharmacist to non-pharmacist in an urban
environment and commercial centre, like Lagos is approximately 1:3, NSAIDs are
sold or ingested without the required level of caution. These unregistered drug
outlets, usually manned by traders, are located virtually in every street of
urban centers in Nigeria.
Evaluation
of drug use revealed that there was a great deal of drug misuse ranging from
sub – therapeutic dosing, wrong indication and irrational combination of drugs,
even in high doses (Awofisayo et al, 2008)
DEFINITION
One
of the conditions that necessitate the use of NSAIDs is pain. Pain is an
unpleasant, subjective sensory and emotional experience associated with actual
or potential tissue damage or described in terms of such damage.
Greater
understanding of pain mechanisms and growing appreciation for pain control
have, however, caused rheumatologists to consider new approaches in pain management..
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Both selective and nonselective
cyclooxygenase (COX) inhibitors have antipyretic, anti-inflammatory and
analgesic effects and are widely used in treating many painful conditions,
including rheumatic diseases. NSAIDs are effective and widely available in
over-the-counter formulations and in prescription products. Examples include ibuprofen,
naproxen, diclofenac, and celecoxib. NSAIDs are frequently used without
considering the relative contraindications since most NSAIDs are sold over the
counter. Conventional NSAIDs are associated with gastrointestinal (GI) side effects.
Estimates of the number of deaths from NSAID-related gastrointestinal bleeding
vary widely and figures of approx. 3500 to 16.500 per year are quoted for the
US in a recent FDA report. Both conventional NSAIDs and COX-2 inhibitors are
associated with increased cardiovascular risk. NSAIDs may increase blood pressure,
particularly in hypertensive patients. Of all NSAIDs, naproxen seems to pose
the least cardiovascular risk, although naproxen is associated with the same
risk for myocardial infarction as other NSAIDs. Contrary to some clinical
assumptions, gastrointestinal risk is present at first dose with a
non-selective NSAID, and co-therapy with a proton pump inhibitor (PPI) does not
guarantee complete protection(Well et al, 2006)
Pain
could be classified into two main groups: NOCICEPTIVE PAIN and NEUROPATHIC PAIN
THE NOCICEPTIVE PAIN
Nociceptive
(acute) pain is either somatic (arising from skin, bone, joint, muscle, or
connective tissue) or visceral (arising from internal organs such as the large
intestine or pancreas).
Stimulation
of free nerve endings known as nociceptors is the first step leading to the
sensation of pain. These receptors are found in both somatic and visceral
structures and are activated by mechanical, thermal, and chemical impulses.
Release of bradykinins, K+, prostaglandins, histamine, leukotrienes, serotonin,
and substance P may sensitize and/or activate nociceptors. Receptor activation
leads to action potentials that are transmitted along afferent nerve fibers to
the spinal cord.
Action
potentials continue from the site of noxious stimuli to the dorsal horn of the
spinal cord and then ascend to higher centers. The thalamus acts as a relay
station and passes the impulses to central structures where pain is processed
further.
The
body modulates pain through several processes. The endogenous opiate system
consists of neurotransmitters (e.g., enkephalins, dynorphins, and beta-endorphins)
and receptors that are found throughout the central nervous system (CNS).
Endogenous opioids bind to opioid receptors and inhibit the transmission of
pain impulses.
The
CNS also contains a descending system for control of pain transmission. This
system originates in the brain and can inhibit synaptic pain transmission at
the dorsal horn. Important neurotransmitters here include endogenous opioids,
serotonin, norepinephrine, gama-aminobutyric acid (GABA), and neurotensin.
NEUROPATHIC
PAIN
Neuropathic
(chronic) pain is sustained by abnormal processing of sensory input by the
peripheral or central nervous system. There are a large number of neuropathic
pain syndromes that are often difficult to treat (e.g., low back pain, diabetic
neuropathy, postherpetic neuralgia, cancer-related pain, spinal cord injury). Nerve
damage or persistent stimulation may cause pain circuits to produce spontaneous
nerve stimulation, autonomic neuronal pain stimulation, and a progressive
increase in discharge of dorsal horn neurons.
The
inflammatory process is the response to an injurious stimulus. It can be evoked
by a wide variety of noxious agents (e.g., infections, antibodies, or
physical injuries). The ability to mount an inflammatory response is essential
for survival in the face of environmental pathogens and injury; in some
situations and diseases, the inflammatory response may be exaggerated and sustained
without apparent benefit and even with severe adverse consequences. No matter
what the initiating stimulus, the classic inflammatory response includes calor
(warmth), dolor (pain), rubor (redness), and tumor (swelling).
Inflammatory
responses occur in three distinct temporal phases, each apparently mediated by
different mechanisms:
(1)
An acute phase characterized by
transient local vasodilation and increased capillary permeability;
(2) A delayed,
subacute phase characterized by infiltration of leukocytes and phagocytic
cells; and
(3)
A chronic proliferative phase, in which
tissue degeneration and fibrosis occur.
Many mechanisms are involved in the promotion and resolution of the
inflammatory process. Although earlier studies emphasized the promotion of
migration of cells out of the microvasculature, recent work has focused on
adhesive interactions, including the E-, P-, and L-selectins, intercellular
adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and
leukocyte integrins, in the adhesion of leukocytes and platelets to endothelium
at sites of inflammation.
Activated endothelial cells play a key role in "targeting"
circulating cells to inflammatory sites. Expression of the adhesion molecules
varies among cell types involved in the inflammatory response. Cell adhesion
occurs by recognition of cell-surface glycoproteins and carbohydrates on
circulating cells due to the augmented expression of adhesion molecules on
resident cells. Thus, endothelial activation results in leukocyte adhesion as
the leukocytes recognize newly expressed L-selectin and P-selectin; other
important interactions include those of endothelial-expressed E-selectin with
sialylated Lewis X and other glycoproteins on the leukocyte surface and
endothelial ICAM-1 with leukocyte integrins. It has been proposed that some,
but not all, NSAIDs may interfere with adhesion by inhibiting expression or
activity of certain of these cell-adhesion molecules . Novel classes of
antiinflammatory drugs directed against cell-adhesion molecules are under
active development but have not yet entered the clinical arena.
In addition to the cell-adhesion molecules outlined above, the recruitment of
inflammatory cells to sites of injury involves the concerted interactions of
several types of soluble mediators. These include the complement factor C5a,
platelet-activating factor, and the eicosanoid LTB4. All can act as chemotactic
agonists. Several cytokines also play essential roles in orchestrating the
inflammatory process, especially interleukin-1 (IL-1) and tumor necrosis factor
(TNF) (Dempsey et al.,
2003). IL-1 and TNF are considered principal mediators of the
biological responses to bacterial lipopolysaccharide (LPS, also called
endotoxin). They are secreted by monocytes and macrophages, adipocytes, and
other cells. Working in concert with each other and various cytokines and
growth factors (including IL-8 and granulocyte-macrophage colony-stimulating
factor, they induce gene expression and protein synthesis in a variety of cells
to mediate and promote inflammation.
IL-1 comprises two distinct polypeptides (IL-1a and IL-1b) that bind to the
same cell-surface receptors and produce similar biological responses. Plasma
IL-1 levels are increased in patients with active inflammation. IL-1 can bind
to two types of receptors, an 80-kd IL-1 receptor type 1 and a 68-kd IL-1
receptor type 2, which are present on different cell types.
TNF, originally termed "cachectin" because of its ability to produce
a wasting syndrome, is composed of two closely related proteins: mature TNF
(TNF-a) and lymphotoxin (TNF-b), both of which are recognized by the same
cell-surface receptors. There are two types of TNF receptors, a 75-kd type 1
receptor and a 55-kd type 2 receptor. IL-1 and TNF produce many of the same
proinflammatory responses.
A
naturally occurring IL-1 receptor antagonist (IL-1ra), competes with IL-1 for
receptor binding, blocks IL-1 activity in vitro and in vivo, and
in experimental animals can prevent death induced by administration of bacteria
or LPS. IL-1ra often is found in high levels in patients with various
infections or inflammatory conditions. Thus, the balance between IL-1 and
IL-1ra may contribute to the extent of an inflammatory response. Preliminary studies
suggest that the administration of IL-1ra (designated anakinra)¾by blocking
IL-1 action on its receptor¾may be beneficial in rheumatoid arthritis and other
inflammatory conditions(Louie et al., 2003; Olson and Stein, 2004).
Other cytokines and growth factors [e.g., IL-2, IL-6, IL-8, and
granulocyte/macrophage colony stimulating factor (GM-CSF)] contribute to
manifestations of the inflammatory response. The concentrations of many of
these factors are increased in the synovia of patients with inflammatory
arthritis. Certain relevant peptides, such as substance P, which promotes
firing of pain fibers, also are elevated and act in concert with cytokines at
the site of inflammation. Other cytokines and growth factors counter the
effects and initiate resolution of inflammation. These include transforming
growth factor-b1 (TGF-b1), which increases extracellular matrix formation and
acts as an immunosuppressant, IL-10, which decreases cytokine and prostaglandin
E2 formation by inhibiting monocytes, and interferon gamma, IFN-g, which
possesses myelosuppressive activity and inhibits collagen synthesis and
collagenase production by macrophages.
Histamine was one of the first identified mediators of the inflammatory
process. Although several H1 histamine-receptor antagonists are available, they
are useful only for the treatment of vascular events in the early transient
phase of inflammation. Bradykinin and 5-hydroxytryptamine (serotonin, 5-HT)
also may play a role in mediating inflammation, but their antagonists
ameliorate only certain types of inflammatory response. Leukotriene
(LT)-receptor antagonists (montelukast and zafirlukast) exert
antiinflammatory actions and have been approved for the treatment of asthma.
Another lipid autacoid, platelet-activating factor (PAF), has been implicated
as an important mediator of inflammation; however, inhibitors of PAF synthesis
and PAF-receptor antagonists have proven disappointing in the treatment of
inflammation.
Intradermal, intravenous, or intra-arterial injections of small amounts of
prostaglandins mimic many components of inflammation. Administration of
prostaglandin E2 (PGE2) or prostacyclin (PGI2) causes erythema and an increase
in local blood flow. Such effects may persist for up to 10 hours with PGE2 and
include the capacity to counteract the vasoconstrictor effects of substances
such as norepinephrine and angiotensin II, properties not generally shared by
other inflammatory mediators. In contrast to their long-lasting effects on
cutaneous vessels and superficial veins, prostaglandin-induced vasodilation in
other vascular beds vanishes within a few minutes.
Although PGE1 and PGE2 (but not PGF2a) cause edema when injected into the hind
paw of rats, it is not clear if they can increase vascular permeability in the
postcapillary and collecting venules without the participation of other
inflammatory mediators (e.g., bradykinin, histamine, and leukotriene
C4 [LTC4]). Furthermore, PGE1 is not produced in significant quantities in
humans in vivo, except under rare circumstances such as essential fatty
acid deficiency. Unlike LTs, prostaglandins are unlikely to be involved in
chemotactic responses, even though they may promote the migration of leukocytes
into an inflamed area by increasing blood flow.
Rheumatoid
Arthritis. Although the detailed pathogenesis of rheumatoid
arthritis is largely unknown, it appears to be an autoimmune disease driven
primarily by activated T cells, giving rise to T cell-derived cytokines, such
as IL-1 and TNF-a. Activation of B cells and the humoral response also are
evident, although most of the antibodies generated are IgGs of unknown
specificity, apparently elicited by polyclonal activation of B cells rather
than from a response to a specific antigen.
Many cytokines, including IL-1 and TNF-a, have been found in the rheumatoid
synovium. Glucocorticoids interfere with the synthesis and actions of
cytokines, such as IL-1 or TNF-a . Although some of the actions of these
cytokines are accompanied by the release of prostaglandins and thromboxane A2 (TXA2),
COX inhibitors appear to block only their pyrogenic effects. In addition, many
of the actions of the prostaglandins are inhibitory to the immune response,
including suppression of the function of helper T cells and B cells and
inhibition of the production of IL-1. Thus, it has been suggested that
COX-independent effects may contribute to the efficacy of NSAIDs in this
setting. Besides an impact on adhesive interactions, salicylate and certain NSAIDs
can directly inhibit the activation and function of neutrophils, perhaps by
blockade of integrin-mediated neutrophil responses by inhibiting downstream Erk
signaling.
The
availability of a wide variety of drugs coupled with easy access and lack of
effective regulatory control has led to problems associated with drug use like
self-medication, drug misuse and drug abuse (Amoako et al 2003). Self
medication: defined as the act of taking medicines or medical devices
especially designed and labeled for use in the treatment of common health
problems without the authority or prescription of a physician (Lawan
et al, 2013). Drug abuse
is the recurrent use of illegal drugs, or the misuse of prescription or
over-the-counter drugs with negative consequences. Hence, drug misuse is an
aspect of drug abuse. This practice cuts across all age groups, gender,
educational backgrounds, marital status, employment and occupation. Pattern of
drug misuse varies from place to place and it is known to be affected by
socio-economic factors (Kehinde and Ogunnowo, 2013).
Self-medication
is the act of taking medicines or medical devices especially designed and
labeled for use in the treatment of common health problems without the
authority or prescription of a physician and it is one of the rapidly growing
areas of concern to medical professionals, government and the general public
(Lawan et al, 2013).
There
is overwhelming evidence linking chronic nonselective NSAID (including aspirin)
use to a variety of Gastrointestinal (GI) tract injuries. Age is a significant risk factor for
NSAID-induced GI events; indeed, patients above 75 years of age carry the
highest risk and are similar in this respect to patients with a history of
peptic ulcer (Berardi and Welage, 2005).
NSAIDs
rank second to aminoglycosides as the most common cause of drug induced renal
failure (ARF) and also known to cause acute interstitial nephritis with haematuria,
proteinuria and flank pain (Welton, 1999).
In
a study carried out in Ghana, about 40% of prescribed analgesics were NSAIDs
and diclofenac was the most widely prescribed (Owusu-Ansah, 2009).
Aspirin
remains the most commonly prescribed NSAIDs in cardiovascular diseases like
hypertension and ischemic heart disease where it is used as antiplatelet
agent(Aguw and Adibe, 2012).
Exposure
of pregnant women to any type of NSAIDs during early pregnancy predispose them
to spontaneous abortion (Li et al, 2003)
A
high proportion of chronic urticarial patients experience symptom aggravation
when exposed to aspirin and NSAIDs known as Aspirin-exacerbated cutaneous
disease (Sánchez-Borges, 2013)
1.2 STATEMENT OF THE PROBLEM
The
use of NSAIDs accounts for an estimated 76 000 hospitalizations and 7600 deaths
in the United States ( Fries, 1992) and 3897 hospitalizations
and 365 deaths in Canada (IMSC, 1997) every year. These
hospitalizations and deaths are majorly due to ulcer and gastrointestinal
bleeding related to NSAID use. Irrational prescribing has further complicated
the adverse effects from the use of NSAIDs.
Asides
gastrointestinal toxicity, renal failure has been recently known to be a risk
if the patient is also concomitantly taking an ACE inhibitor and a diuretic -
the so-called “triple whammy” effect. Liver problems are also
possible with the long term use of NSAIDs (Awodele et al, 2015).
1.3 JUSTIFICATION OF THE STUDY
Self-medication is widespread all over the
world and occurs in both urban (Pandy et al, 2013) and rural
population (Bello and Bello, 2013). Pharmacies and patient medicine
stores are visible in both urban and rural settlements in the study area
suggest access of people to various types of drugs. These medications may be
acquired with or without recommendation from qualified medical practitioners.
The potential of NSAIDs to cause significant unwanted effects for users
especially when taken in high doses and for prolonged duration, necessitates
this study. The new trend in pharmacy practice entails appropriate guide in
medication use (Isetts and McGann,
2012)
1.4 STUDY OBJECTIVES
The
general objective of this study was To evaluate rationale
use of NSAID in Ilorin metropolis
The specific objectives
of this study include to:
1.
Assess
the level of prevalence and pattern of misuse of NSAIDS among the residents of Ilorin
2.
Describe the Prescribing pattern of NSAIDs
among prescribers in the University of Ilorin Teaching Hospital.
3.
Assess the Dispensing pattern of NSAIDs
among the Community Pharmacists in Ilorin metropolis
4.
Determine factors that influence misuse of
NSAIDs among the residents.
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