**3. Ibuprofen**

Ibuprofen was introduced to the US market as a prescription drug to treat arthritic conditions in 1974, and subsequently became available over the counter in the United States in 1984. Despite its relatively short history as an over-the-counter medicine, it has quickly achieved popularity as a treatment for musculoskeletal and peripheral nerve pain, capturing up to a third of the over-the-counter analgesics market of the US by 2002. According to background information supplied by Wyeth Pharmaceuticals (a manufacturer of Advil, a brand name ibuprofen), this occurred principally because of its strong gastrointestinal (GI) safety profile that ibuprofen was approved for over-the-counter use. There are a wide variety of ibuprofen drugs available on the market as indicated in **Table 1**. Tablet, caplet, injectable, and topical forms are available. Negative side effects and major concerns will be discussed later in this chapter, although it should be noted that topical ibuprofen formulas are absorbed less into blood stream than oral forms, avoiding several side effects. However, as topical NSAID drugs are not systemic, they will not reduce inflammatory responses other than at the site of application.

Ibuprofen works by inhibiting both the constitutive cyclooxygenase (COX)-1 and the more inducible COX-2 enzyme. These enzymes catalyze the generation of prostanoids ( prostaglandins PGE2 and PGF2a), prostacyclins, and thromboxanes [25, 26]. Inhibition of these enzymes by ibuprofen prevents the conversion of arachidonic acid to prostaglandin H2, and in doing so blocks the prostaglandin-signaling pathway. Prostaglandins play an important role in pain and inflammatory signaling, as well as have roles in maintaining kidney function (mainly by regulating blood flow in the glomerular capsule) and the gut mucosa, and cardiovascular physiological processes [26].

#### **Brand names**

ties, and are a leading cause of pain and physical disability [1–4]. Some cases become so severe that simple personal tasks, such as buttoning a shirt, become difficult to impossible. Acute trauma may be a causal factor in some WMSDs. Yet, many result from cumulative small amplitude forces occurring with overtraining, overexertion, repetitive activities, forceful actions, and prolonged static positioning [5–8]. Prevention is hampered by many problems [9, 10]. There

The first line of treatment for workers in pain usually entails a prescription of non*-*steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen [12, 13]. NSAIDs are the most commonly used (self-care and prescribed) for acute and chronic musculoskeletal pain [14–17]. A survey study of 941 workers found that 84% used NSAIDs, including ibuprofen, for pain [17]. Forty percent of 2213 French workers reported the regular use of ibuprofen in a 1-month period [18]. Back and shoulder injuries and other musculoskeletal strains are largely selftreated by migrant farm workers with rest and over-the-counter drugs, such as ibuprofen [14]. Rest, ice, compression, and elevation (termed RICE oftewn) are also often used to treat acute injuries. However, RICE has proved less effective for treatment of pain associated with chronic overuse—MSDs than NSAIDs. Splinting for carpal tunnel syndrome is less effective than surgical release or injections of steroids around the nerve [19–24], which are also not

Ibuprofen was introduced to the US market as a prescription drug to treat arthritic conditions in 1974, and subsequently became available over the counter in the United States in 1984. Despite its relatively short history as an over-the-counter medicine, it has quickly achieved popularity as a treatment for musculoskeletal and peripheral nerve pain, capturing up to a third of the over-the-counter analgesics market of the US by 2002. According to background information supplied by Wyeth Pharmaceuticals (a manufacturer of Advil, a brand name ibuprofen), this occurred principally because of its strong gastrointestinal (GI) safety profile that ibuprofen was approved for over-the-counter use. There are a wide variety of ibuprofen drugs available on the market as indicated in **Table 1**. Tablet, caplet, injectable, and topical forms are available. Negative side effects and major concerns will be discussed later in this chapter, although it should be noted that topical ibuprofen formulas are absorbed less into blood stream than oral forms, avoiding several side effects. However, as topical NSAID drugs are not systemic, they will not reduce inflammatory responses other than at the site of

Ibuprofen works by inhibiting both the constitutive cyclooxygenase (COX)-1 and the more inducible COX-2 enzyme. These enzymes catalyze the generation of prostanoids ( prostaglandins PGE2 and PGF2a), prostacyclins, and thromboxanes [25, 26]. Inhibition of

remains a call for effective treatments for these often debilitating disorders [9, 11].

**2. Current treatments for overuse—MSDs**

always effective [19–24].

**3. Ibuprofen**

182 Occupational Health

application.

**Active ingredient:** Ibuprofen (100–800-mg tables and caplets available). **Typical dose** is 200–400 mg/dose; Maximum amount is 800 mg/dose, or 3200 mg per day. **Use:** Reduction of fever, pain, or inflammation from headache, dental pain, menstrual cramps, rheumatoid arthritis, osteoarthritis, muscle aches, minor aches, and pain. **Note:** An anti-inflammatory dose is higher than an analgesic dose, and must be maintained for full effectiveness.

**Ibuprofen PM Tablets:** Advil PM, Motrin PM

**Active Ingredient:** Ibuprofen (200 mg) and Diphenhydramine citrate (38 mg). **Typical dose** is two capsules at bedtime (also the maximum dose/day). **Use:** Occasional sleeplessness when associated with minor aches and pains.

#### **Injectable Ibuprofen:** Caldolor, Calprofen (UK), and more

**Active Ingredient:** Ibuprofen (various doses available). **Typical dose**: Intravenous infusion of 100–800 mg dose, after dilution to 4 mg/ml or less per injection. **Use:** Reduction of fever; Management of mild to moderate pain, and moderate to severe pain as an adjunct to opioid analgesics.

**Topical Ibuprofen:** Ibuprofen Gel (US), Ibuleve gel (UK), Ibumousse (UK), Ibuspray (UK), and more

**Active Ingredient:** Ibuprofen (various doses available).

**Typical dose:** three to four times a day, or as directed by a doctor, with at least 4 h between applications. **Use:** Muscle or rheumatic pain, backache, neuralgia; sprains, strains and sports injuries; mild arthritis. **Note:** Absorbed less into blood stream when applied topically, so not thought to reduce fever or widespread inflammation as a consequence.

**Table 1.** Types of ibuprofen available.

A steady dose of ibuprofen is considered necessary to attenuate the increase in inflammation, rather than just analgesic. The dose used should be lower than the maximum limit for gastrointestinal toxicity. Those suggested maximum limits are indicated in **Table 1**.

#### **4. An operant rat model of WMSD**

Several animal models have been developed to study WMSDs and have shown that repetitive hand activities induce sensorimotor dysfunction [27–33]. A model developed in our

**Ibuprofen Tablets and Caplets:** Actiprofen Caplets (CA), Advil, Advil Extra Strength (CA), Advil Migraine, Anadin Ibuprofen (UK), Anadin Ultra (UK), Apo-Ibuprofen (CA), Arthrofen (UK), Brufen (UK), Cuprofen (UK), Extra Strength Motrin IB (CA), Hedex Ibuprofen (UK), Motrin, Motrin IB, Ibuprofen (CA), IBU

laboratory is a unique operant rat model of voluntary reaching and grasping (**Figure 1**; [7, 34]). Using this model, we are able to examine the effects of voluntary performance of repetitive low or high demand tasks on sensorimotor performance and musculoskeletal tissues [7, 30, 35]. This model is nonsurgical and involves performance of voluntary repetitive tasks to induce mechanical loading of forearm tissues. Specifically, adult rats are required to voluntarily and repetitively reach for, grasp, and isometrically pull a handle with one forelimb to obtain a food reward at various reach rates and force levels determined from studies on risk exposure for WMSDs to humans [7, 34]. Additionally, several functional outcomes are tested that are similar to those tested in patients, including forepaw (hand) sensitivity, grip strength, and median nerve conduction velocity.

Using this rat model, we have observed early exposure-dependent changes (duration and task level) in inflammatory responses in the form of increased macrophages and inflammatory cytokines in soft tissues involved in performing the repetitive task [7, 30, 32, 35, 36]. The greatest responses were observed in rats performing a high-repetition high-force (HRHF) task for 6–12 weeks, compared to lower demand tasks. Therefore, we picked this HRHF task regimen for experiments in which we tested the effectiveness of ibuprofen.

**Figure 1.** Rat performing HRHF repetitive reaching task. (A) Rat awaits auditory stimulus with snout in portal. (B and C) Rat reaches for force handle with right forepaw; left forepaw used for postural support. (D) Closer view, rat grasps and isometrically pulls force handle attached to force transducer (FT), until predetermined force threshold is reached and held for at least 50 ms. (E) Rat retrieves foot pellet reward by mouth from food trough.
