**3.3 Contraindications of NSAIDs**

There are many contraindications of this drug class presented on below (**Table 3**) [23].

## **3.4 Efficiency of the NSAIDs**

The number needed to treat (NNT, basically the number of patients in a study to whom the drug must be given to show a benefit) for diclofenac 50 mg 2.3, ketorolac 10 mg is 2.6 and ibuprofen 400 mg 2.4. For comparison, the NNT of morphine 10 mg


IM is 2.9 and codeine 60 mg PO is 16.7. When given in combination with opioids, NSAIDs optimise the pain control and decrease opioid consumption by 25–50% [2]. NSAIDs are insufficient as a single pain killer use for relief of very severe pain.

COX-2 inhibitors produce less clinically significant peptic ulceration than other NSAIDs. So, COX-2 inhibitors are not far from any incidence of this adverse event, and there still debates on COX-2 inhibitors use in patients who have various risk factors for gastric erosion.

Platelets do not produce COX-2 (only COX-1) and so, COX-2 selective inhibitors do not affect platelet function. Studies have proved the lack of and antiplatelet effect of COX-2 inhibitors, and a reduction in surgical bleeding in comparison to other NSAIDs.

COX-2 is resident (constitutive) in some tissues including the renal, and COX-2 inhibitors have similar adverse effects on renal function to the non-selective NSAIDs (**Table 4**) [2].

#### **3.5 Drug interactions**

*Aspirin.* NSAIDs may impair the cardioprotective feature of aspirin, but this subject is still debatable lacking of strong evidences against use of NSAIDs for acute pain or inflammation in a patient on chronic daily aspirin use [24, 25].

*Oral Anticoagulants.* NSAIDs have an antiplatelet effect, added to the anticoagulant properties of warfarin, is exponential increasing the risk of significant bleeding complications, especially from the GI ulcers. Furthermore, NSAIDs displace proteinbound warfarin and is leading to increase the prothrombin times during a constant warfarin dose [18]. NSAIDs should be avoided in patients who are taking warfarin.

*ACE Inhibitors.* Concomitant use of NSAIDs with ACE inhibitors may impair kidney function and may prejudice the antihypertensive effect of ACE inhibitors.

*Diuretics.* Patients on diuretics have a higher risk of developing renal failure because of NSAIDs-mediated decreased kidney blood perfusion. Also, the natriuretic response to diuretics is in relation with prostaglandin-mediated vasodilatation.

*Glucocorticoids.* Patients on corticosteroids possess a higher risk of peptic ulcer. NSAIDs should be avoided in patients concomitantly taking corticosteroids unless closely supervised.


**243**

**Table 5.**

*Opioids receptors end their effects.*

*Analgesics*

*DOI: http://dx.doi.org/10.5772/intechopen.94319*

elimination of methotrexate.

**4. Opioid analgesic agents**

reduced in patient concurrently taking NSAIDs.

centuries, as their toxicity and also the potential for abuse.

opioids are often inadequate used in clinical practice [27, 28].

Miu 1 Euphoria, supraspinal analgesia, confusion, dizziness, nausea, low addiction potential

Delta Spinal analgesia, CV depressions, decreased brain and myocardial activity, physical dependence

Kappa Spinal analgesia, dysphoria, psychotomimetic effects,

feedback inhibition of the endorphin system

Epsilon Hormone Beta-endorphin Gamma Dysphoria, psychotomimetic effects Beta-endorphin

Miu 2 Respiratory depression, CV and GI effects, miosis,

urinary retention

**4.1 Mechanism of action and toxic effects**

the agent to the various receptors (**Table 5**).

**Opioid receptor** 

**class**

*Lithium.* NSAIDs increase lithium reabsorption and may reduce lithium excretion, and cause subsequently increases lithium levels. CNS manifestations (confusion, drowsiness, vertigo, tremors, seizures), QRS complex widening and cardiac arrhythmias are warning signs of lithium toxicity. The lithium doses should be

*Methotrexate.* Chronic use of NSAIDs and methotrexate have resulted in prolonged, increased levels of methotrexate, leading to severe toxicity. A possible mechanism is accountable due to decreased renal blood supply, slowing down the

In 1680, Sydenham wrote "Among the remedies it has pleased Almighty God to give to man to relive his suffering, none is so universal and so efficacious as opium" [2, 26]. Hundreds of years later, this statement is still valid, and opioids are the cornerstone of pain management. The beneficial effects have been well studied for

Opioid analgesics are usually used to relieve moderate to severe pain particularly of visceral origin. Repeated administration may cause dependence and tolerance, but this is not deterrent in the pain control of terminal illness. Regular use of a potent opioid may be appropriate for certain cases of chronic non-malignant pain; treatment should be supervised by medical staff and the patient should be assessed regularly. However, due to concerns about inducing opioid toxicity or addiction and sometimes due to poor understanding of the pharmacology features of these drugs,

Opioids bind to specific endorphin system receptors located throughout the nervous system but not only. Opioid receptors are G-protein-coupled transmembrane receptors. These exist throughout the CNS, with particularly high concentration in thalamus and spinal cord. They are also present outside the CNS, and these are responsible for other opioids effects (gastrointestinal tract) and their postulated value in some peripheral anaesthetic techniques, such as intra-articular infiltrations [6]. The actions of various opioids are induced by the specific binding properties of

**Effects Associated endogenous** 

**endorphin**

Beta-endorphin

Beta-endorphin

Enkephalin

Dynorphin, Beta-endorphin

#### **Table 4.**

*Comparison of non-selective NSAIDs and COX-2 inhibitors.*

#### *Analgesics DOI: http://dx.doi.org/10.5772/intechopen.94319*

*Pain Management - Practices, Novel Therapies and Bioactives*

IM is 2.9 and codeine 60 mg PO is 16.7. When given in combination with opioids, NSAIDs optimise the pain control and decrease opioid consumption by 25–50% [2]. NSAIDs are insufficient as a single pain killer use for relief of very severe pain.

COX-2 inhibitors produce less clinically significant peptic ulceration than other NSAIDs. So, COX-2 inhibitors are not far from any incidence of this adverse event, and there still debates on COX-2 inhibitors use in patients who have various risk fac-

Platelets do not produce COX-2 (only COX-1) and so, COX-2 selective inhibitors do not affect platelet function. Studies have proved the lack of and antiplatelet effect of COX-2 inhibitors, and a reduction in surgical bleeding in comparison to other NSAIDs. COX-2 is resident (constitutive) in some tissues including the renal, and COX-2

inhibitors have similar adverse effects on renal function to the non-selective

pain or inflammation in a patient on chronic daily aspirin use [24, 25].

*Aspirin.* NSAIDs may impair the cardioprotective feature of aspirin, but this subject is still debatable lacking of strong evidences against use of NSAIDs for acute

*Oral Anticoagulants.* NSAIDs have an antiplatelet effect, added to the anticoagulant properties of warfarin, is exponential increasing the risk of significant bleeding complications, especially from the GI ulcers. Furthermore, NSAIDs displace proteinbound warfarin and is leading to increase the prothrombin times during a constant warfarin dose [18]. NSAIDs should be avoided in patients who are taking warfarin. *ACE Inhibitors.* Concomitant use of NSAIDs with ACE inhibitors may impair kidney function and may prejudice the antihypertensive effect of ACE inhibitors. *Diuretics.* Patients on diuretics have a higher risk of developing renal failure because of NSAIDs-mediated decreased kidney blood perfusion. Also, the natriuretic response to diuretics is in relation with prostaglandin-mediated vasodilatation.

*Glucocorticoids.* Patients on corticosteroids possess a higher risk of peptic ulcer. NSAIDs should be avoided in patients concomitantly taking corticosteroids unless

**NSAIDs COX-2**

Celecoxib 200 mg (4.5) Parecoxib 20 mg (3.0) Etoricoxib 120 mg (1.8)

> Less clinically significant peptic ulceration

Do not impair platelet function

> Do not produces bronchospasm

Similar to NSAIDs

Diclofenac 50 mg (2.3) Ibuprofen 400 mg (2.4) Ketorolac 10 mg (2.6)

can occur. Risk increased with higher doses, history of GI ulceration, long term use, and elderly

significantly increase surgical blood loss in normal patients. Associated with higher incidence of post-tonsillectomy bleeding

10–15% of asthmatics affected when given aspirin. Cross-sensitivity with NSAIDs

evidences that clinically important

*Renal function* Can impair renal function postoperatively Similar adverse effects

*Gastrointestinal* Acute gastrointestinal damage and bleeding

*Platelet function* Inhibit platelet function but do not

*Bone healing* Impaired in animal studies. No strong

*Comparison of non-selective NSAIDs and COX-2 inhibitors.*

**242**

**Table 4.**

Efficacy for moderate to severe acute pain (numbers

tors for gastric erosion.

NSAIDs (**Table 4**) [2].

**3.5 Drug interactions**

to treat – NNT)

closely supervised.

*Aspirin-exacerbated respiratory disease*

*Lithium.* NSAIDs increase lithium reabsorption and may reduce lithium excretion, and cause subsequently increases lithium levels. CNS manifestations (confusion, drowsiness, vertigo, tremors, seizures), QRS complex widening and cardiac arrhythmias are warning signs of lithium toxicity. The lithium doses should be reduced in patient concurrently taking NSAIDs.

*Methotrexate.* Chronic use of NSAIDs and methotrexate have resulted in prolonged, increased levels of methotrexate, leading to severe toxicity. A possible mechanism is accountable due to decreased renal blood supply, slowing down the elimination of methotrexate.
