If pain is the most common and troublesome symptom of arthritis, fatigue runs a close second. Often the two are closely related. Dealing with pain day to day can wear you down and cause fatigue. Being fatigued, in turn, can worsen pain and make it more difficult to manage.

There are many reasons for the fatigue that often comes with arthritis pain. One is the disease process itself. The inflammatory cytokines (proteins in the blood) that are released in arthritis are the same ones that are released when you have a bad cold or the flu. Regardless of what triggers their release, the result is the same – fatigue.

The presence of inflammation is “quite significant” in terms of therapy for fatigue, says David Pisetsky, MD, PhD, chief of the Division of Rheumatology and Immunology at Duke University Medical Center and director of the Duke University Arthritis Center. In the absence of uncontrolled inflammation or if treating inflammation fails to relieve fatigue, doctors will consider these other possibilities:

Medication side effects. Some medications, including those for pain, are associated with fatigue. Common culprits include certain antidepressants, blood pressure medication, sleep aids, narcotic analgesics, and even some prescription nonsteroidal anti-inflammatory drugs (NSAIDs). Corticosteroids may cause daytime fatigue by keeping you awake at night.

Anemia. Fatigue in arthritis often results from anemia – a lack of red blood cells. The anemia may result from a peptic ulcer induced by a medications such as NSAIDs or due to the disease process itself,” says Robert Shaw, MD, a rheumatologist in Westminster, MD, and instructor of medicine at Johns Hopkins School of Medicine. Up to two-thirds of people with arthritis have a condition called anemia of inflammation, or anemia of chronic disease, which occurs when inflammatory cytokines interfere with the body’s production of red blood cells, which carry oxygen to the body’s tissues.

Lack of sleep. If pain makes it difficult to get to sleep or wakes you up in the night, the result can be daytime fatigue. A study conducted by the University of North Carolina at Chapel Hill found that lost sleep was what prompted most arthritis patients to seek medical care. When fatigue from inflammation has been ruled out, Dr. Shaw commonly refers his patients to sleep studies to rule out another common problem: sleep apnea, a condition in which breathing is interrupted during sleep.

Depression. Arthritis pain can rob you of the ability to take part in your normal daily activities, so it’s no surprise depression often goes hand-in-hand with the disease. However, research shows depression may also result from fluctuations of hormones and neurotransmitters caused by dealing with the stress of a chronic illness.

Other medical conditions. One major indirect cause of pain in arthritis, fibromyalgia, is also one of the biggest causes of fatigue. Having arthritis may increase your risk of other health problems, such as heart and lung disease and other autoimmune diseases, including autoimmune hypothyroidism, which can be associated with fatigue.