Falls and Fractures in Older Post-Stroke Patients with Spasticity: Consequences and Drug Treatment Considerations

Alberto Esquenazi, MD

Falling is a common complication of stroke, particularly in patients with symptomatic hemiparesis and spasticity.3 It is the most common cause of injury among stroke patients in the acute care and home settings.3,4 Falls resulting in injuries are a leading cause of morbidity, mortality, immobility, and health care expenditures, particularly among the elderly.5 It is estimated that 84% of bone fractures sustained by stroke patients are caused by falls.6 The risk of hip fracture in stroke patients is fourfold that of the general population.7

A report conducted by Ramnemark and colleagues7 found that the prevalence of previous strokes among patients age 65 and older with femoral neck fractures increased significantly (P < 0.001) from 1980-1997 and ranged from 16.4-38.5%. Noninjurious falls may reduce quality of life, increase caregiver burden, and decrease patients’ willingness to participate in activities of daily living due to fear of falling again.8 Additionally, patients with a history of falling are at an increased risk for future functional dependence and hospitalizations.9 Stroke may result in an upper motor neuron syndrome characterized by spasticity, muscle weakness, and a variety of motor control abnormalities that impair the regulation of voluntary movement.10 Spasticity may negatively affect balance, mobility, and gait, possibly increasing risk of falls and bone fractures.11

The problem is exacerbated by use of centrally sedating medications that have antispasticity effects—such as tranquilizers, calcium-channel blockers, and phenothiazines—but that predispose patients to an increased relative risk of falls when compared with patients not taking these medications.11-13 Appropriate management of spasticity is thus an important goal in the care of post-stroke patients, and may reduce incidence and cost of expensive and probably avoidable events such as falls and fractures.

Social and Resource Consequences of Falls and Fractures

Up to 83% of all falls in rehabilitation hospitals involve stroke patients.14 Risk is increased by several factors associated with stroke, including history of previous stroke, disability of the lower extremities, musculoskeletal conditions, muscle weakness, use of major tranquilizers or sedative medications, and problems with balance, mobility, and gait.8,12-15 Injury, often from falling, is the sixth leading cause of death in persons older than 65 years of age.11

In a prospective, observational study of elderly community members, of those who fell, 24% suffered a serious injury and 6% experienced a fracture. Almost 50% of those who fell were afraid of falling again, with 26% of them curtailing activities because of their fear.11 Additionally, a survey of community-dwelling women 65 years of age and older found that women taking central nervous system (CNS)-active medications such as benzodiazepines, antidepressants, and anticonvulsants were at increased risk of frequent falling.16 Should the fear of falling lead to increasing immobilization, other comorbidities such as muscle weakness, joint contractures, and disuse osteoporosis may occur.  

One of the most debilitating and costly consequences of falls related to stroke is sustaining a fracture—particularly a hip fracture,17,18 which typically occurs in elderly individuals with decreased bone density.18 Hip fractures are a common and serious complication of stroke, usually affecting the paretic side and often occurring within the first year after a stroke.4,6 Stroke patients with hemiplegia may suffer from disuse osteoporosis, further increasing their risk of fracture if they fall.4 One-year mortality rates after a fracture of the hip have been reported and range from 14-36%.19 Care of patients with hip fractures is costly. The economic burden is expected to grow as the average age of the U.S. population increases.

Up to 39% of patients with hip fractures become permanent residents in skilled nursing facilities during the year after sustaining a fracture.18  The cost for care of a patient with hip fracture has been estimated to be from $19,000 to over $40,000 for the first year.18 In 1992, the total cost of hip fracture care was almost $9 billion.18 Hip fracture costs are anticipated to increase exponentially because of the precipitous increase in the elderly population. Using current estimates, the number of hip fractures in the United States will double to 512,000 by 2040. Assuming a 5% rate of inflation, it is estimated that hip fractures will cost the United States $240 billion in 2040.18  Studies evaluating the cost of hip fractures in other countries report similar data, suggesting an international problem that contributes significantly to health care expenditures worldwide.18,20-22 It is estimated that, worldwide, the number of individuals over 64 years of age will increase from 323 million (1999) to 1.56 billion by 2050, with the number of hip fractures expected to reach 6.2 million.18 

This trend has alarming implications for incidence of falls and fractures and associated costs of treatment. Medicare and a variety of international organizations have focused guideline development on preventing falls and fractures, and more work in addressing these risks in post-stroke pharmacologic management is needed. Several case control-studies have shown an association between falls and medication use.8 Medications that increase the risk of falls likely increase the risk of injury, and thus these agents may contribute to growing health care costs.

Impact of Spasticity on Falls

Stroke may result in an upper motor neuron syndrome characterized by spasticity, muscle weakness, and motor control abnormalities that impair regulation of voluntary movement.10 Therefore, the treatment of spasticity may be an important factor in the prevention of falls. Spasticity is not unique to stroke, but also results from other disorders and diseases of the CNS. Effects can be generalized, regional, and/or focal, depending on extent and cause. General spasticity is diffuse and is associated with traumatic brain injury and multiple sclerosis. Regional spasticity affects a large region of the body and is associated with injuries (eg, to the spinal cord). Focal spasticity associated with stroke is due to isolated (local) motor disturbance. Overlap is also possible. Spasticity is characterized by positive and negative symptoms.2,23 Positive symptoms include exaggerated reflexes, rigidity, dystonia, and flexor and extensor spasms that are often painful.

Negative symptoms such as weakness, fatigue, and slow initiation of movement also occur. Contractures result when tone-dependent joint restrictions on range of motion lead to fixed deformity at the joint, requiring surgical intervention. Muscle weakness and loss of balance combined with hypertonia and other aspects of spasticity predispose patients to falls and fractures.

According to the American Geriatrics Society Guideline for the Prevention of Falls in Older Persons,24 older patients with more than one factor predisposing them to fall are at a substantially increased risk for frequent falling. Generally, positive symptoms are more amenable to pharmacologic treatment than negative symptoms,23 but patients should have their medications reviewed as some agents have effects that may exacerbate fall risk.24 An important goal in the management of patients with spasticity involves restoration of normal limb position and ease of passive and/or active movement, with the aim of improving functional outcomes such as the ability to carry out activities of daily living.

A logical focus of pharmacologic management would be treatment of the positive symptoms of spasticity in the hemiparetic post-stroke population. However, targeted therapy based on individual patient need is beneficial.23 Spasticity can significantly hamper activities of daily living, adversely affect patient quality of life, contribute to increased caregiver burden,10,23,25 and may necessitate admission to a long-term care or rehabilitation facility. In addition, patients with spasticity may limit social interactions because of embarrassment. In a survey by Solomon and colleagues,26 patients ranked a severe motor disorder as a consequence of stroke worse than death. Fatigue is also an important consequence of stroke that contributes to functional limitations. In one survey, 40% of stroke patients ranked fatigue, which is exacerbated by the adverse events of oral antispasticity agents, as one of their worst symptoms.These patients strongly linked fatigue to lack of achievement of functional goals.27

Treatment of Spasticity

Physiotherapy alone has not been shown to reduce spasticity or the number of falls.28 Management of patients with spasticity is multifactorial and may include physical therapy, occupational therapy, bracing, pharmacotherapy, and, in severe cases, surgical intervention (Figure).10,29 Physical therapy alone or in conjunction with bracing may be sufficient for the treatment of mild spasticity. Pharmacotherapy may be indicated in moderate-to-severe spasticity (Table).29-31 The addition of oral antispasticity medications, however, may cause systemic weakness, central sedation, and dizziness, thus increasing the risk for falling.29-31 

In addition, these agents can exacerbate the physical disabilities associated with spasticity, as well as the cognitive and affective deficits present in stroke patients. Treatment should facilitate rehabilitation, reduce disability, and alleviate postures or movements that may increase the risk of falling. Effects of central sedating medications can contribute to postural and cognitive instability and increase the risk of falling. Treatment for spasticity targeted to the affected muscle groups of the hemiparetic limb relieves muscle overactivity locally. Focal treatment thus avoids aggravating underlying systemic weakness, is not associated with sedating effects or dizziness, and potentially improves long-term outcomes by reducing the risk of falls. Preferred treatment should have a long duration of action and be cost-effective and convenient to administer.

For the older patient population, in whom polypharmacy is common, those making treatment decisions should consider the potential for drug interactions among commonly used medications. Systemic or oral treatments are appropriate for treating general spasticity typically seen with anoxic brain injury, multiple sclerosis, and spinal cord injury. Regional treatment is indicated for treating regional spasticity, which is typically seen with spinal cord injuries. Stroke-related spasticity is most amenable to focal treatment. Although minimizing therapeutic misadventures produced by centrally acting oral agents in this brittle population is important, oral medications do have a role in treatment of post-stroke patients. In some cases, combination therapy may be necessary to make reduction of oral dosages of antispasticity drugs possible. Treatment decisions should always be made on the basis of the unique needs of each patient.

Comprehensive evaluations of patients’ symptoms and disabilities coupled with a good medical history should help guide treatment. Systemic treatment Systemic agents are most appropriate when overall generalized reduction of muscle tone is necessary.31 Several oral agents are available for this type of treatment. Baclofen is a CNS depressant that possibly works via the GABAB receptors. Sedation, hypotension, dizziness, and nausea and vomiting are among the most common adverse events (AEs) of this agent.31 Benzodiazepines act at the GABAA receptors, with the most common AEs being sedation and depression. These agents must be used cautiously in elderly patients because of the increased risk of AEs resulting from reductions in clearance or metabolism.30,31 Tizanidine is a centrally acting alpha 2-adrenergic agonist with muscle relaxant properties. It too must be used cautiously in elderly patients because of significant risk of hypotension, sedation, generalized weakness and falls, reduced renal clearance, and the potential for hepatotoxicity.32

Sedation, generalized weakness, and dry mouth occur in almost 50% of all patients on tizanidine.32 In clinical trials, these AEs were severe enough to necessitate withdrawal of 17-28% of the patients with spasticity receiving tizanidine.32,33 Finally, dantrolene works directly at the site of the muscle spindle. Generalized weakness, sedation, dizziness, and hepatotoxicity have been reported with the use of this agent.34 Although initially appearing less expensive in terms of acquisition costs, each oral agent has the potential to cause side effects such as hepatotoxicity (which requires periodic blood work follow-up), sedation, and weakness that can worsen both postural and cognitive instability in stroke patients with spasticity and can increase risk of falls and fractures.

Furthermore, these agents must be used cautiously in elderly patients because of reduced renal or hepatic clearance that may lead to increased AEs and contribute to the problem of polypharmacy in this population. These agents should be reserved as second-line or adjunct treatment of spasticity after stroke. Regional treatment Intrathecal baclofen is an option for regional control of spasticity in which more than one limb segment is affected, particularly in conditions such as spinal cord injury or multiple sclerosis.35,36 Intrathecal baclofen has also recently been shown to reduce spastic hypertonia resulting from stroke.37 

Importantly, this tone reduction was associated with improved function in some patients. This variation of baclofen is administered directly into cerebrospinal fluid via a surgically implanted pump. The intrathecal route is used to limit some of the systemic AEs; however, sedation and weakness may still occur.30,31 This treatment may also cause regional tone reduction in both lower limbs, thus exacerbating global weakness and limiting the agent’s use in the treatment of more hemiplegic conditions that affect the majority of the stroke population. There have been reports of complications related to the placement of the pump.35 

Focal treatment
Phenol and alcohol. Phenol and alcohol are injected directly into the nerve or motor point and cause nonselective soft-tissue lysis and neurolysis, blocking effective transmission of nerve impulses to the muscles.38,39 This treatment offers the advantages of a localized effect at a relatively lower cost. Duration of effect ranges from several weeks to more than 6 months. Repeat injections of alcohol or phenol are not always possible because they cause tissue lysis and destruction. Furthermore, scar tissue proliferates and makes repeat treatments more difficult. The most frequent AEs associated with phenol or alcohol nerve block are local pain, swelling, and the potential for dysesthesias caused by incomplete neurolysis of sensory fibers in mixed nerves. Duration of effect is more variable; thus, these agents should not be used if nerve block is desirable for a limited time. For example, if it were necessary to control the severe spasticity that may occur in the early recovery stages following a stroke, for which regular reassessment of the condition is needed, phenol may not be appropriate; an agent with a more predictable duration of action would be indicated.23,29

Botulinum toxin type A. Botulinum toxin type A is a focal treatment for stroke-related spasticity and other conditions, including pediatric cerebral palsy, traumatic brain injury, and a variety of dystonias and movement disorders such as blepharospasm and cervical dystonia.40,41 Botulinum toxin type A is injected directly into the affected muscle groups, usually with electromyographic or electrical stimulation guidance, where it causes reversible, dose-dependent muscle relaxation by blocking acetylcholine transmission at the neuromuscular junction. Patients may typically experience benefits 3-7 days after injection.2 The duration of action in stroke patients is about 3-4 months, after which reinjection is indicated. Some data have suggested that botulinum toxin type A may affect cortical reorganization in a manner similar to physical therapy.40,42 In a double-blind study conducted by Brashear and coauthors,2 126 patients were randomized to receive either botulinum toxin type A or placebo for the treatment of upper-limb spasticity following stroke. Botulinum toxin type A treatment produced benefits in flexor spasticity and improvements in function.2

An open-label follow-up of the double-blind study showed that the duration of the beneficial effects became longer when subsequent treatments were administered.43 Botulinum toxin type A acts locally, minimizing the risk of systemic AEs.42 The most common AE is short-lasting pain at the injection site. In a small percentage of patients (< 1%), the development of neutralizing antibodies to the neurotoxin on repeated injection may reduce or eliminate clinical benefit. The potential for development of neutralizing antibodies is diminished by using the lowest effective dose with treatment intervals of 3 or more months and the toxin with the smallest protein load.44 For management of patients with ankle equinus or ankle equinovarus, botulinum toxin type A is an effective intervention.45,46

The injection of the musculi gastrocnemius, soleus, and, if indicated, the tibialis posterior or anterior should relieve muscle overactivity, which results in improved foot posture during the swing and stance phases of gait and facilitates bracing.47-49 Botulinum toxin type A injection (musculi rectus femoris, vastus medialis, and vastus lateralis) to the knee extensors is an effective focal treatment of stiff knee gait that may result in increased knee flexion in the early swing phase, thus reducing toe drag in the swing phase of gait and allowing the use of compensatory increase in toe clearance when dealing with obstacles.50 

Post-stroke patients often have focal spasticity and underlying weakness. A regimen that improves gait, mobility, and balance may help reduce the risk of falls and fractures and allow an increase in activities of daily living. Optimal pharmacologic management of spasticity should facilitate restoration of motor function and limb posture while not exacerbating the risk of falling due to systemic sedation or weakness. The focal treatment of spasticity with associated decrease in muscle tone and overactivity without sedation, dizziness, and cognitive deficits may significantly reduce the risk of falls and fractures.

Cost of Treatment

Pharmacoeconomic evaluations of the available treatments for spasticity are limited. Botulinum toxin type A may appear at first to be more costly than other spasticity treatments. However, because of its efficacy, lack of serious AEs, ability to be used repeatedly in the same muscles with equal and sometimes increased effect over time, ease of application, and favorable duration of action, botulinum toxin type A may lower the overall costs of treatment.51,52 Two pharmacoeconomic analyses directly compared the cost-effectiveness of botulinum toxin type A and oral baclofen for the focal treatment of spasticity after stroke and traumatic brain injury.52,53 Both studies demonstrated increased effectiveness of botulinum toxin type A and increased costs due to AEs associated with oral baclofen.52,53 Radensky and colleagues52 reported that botulinum toxin type A reduced total costs of managing upper extremity spasticity, and that use of botulinum toxin type A was associated with fewer total treatments due to longer duration of action and decrease in treatment intensity.

A study of intrathecal baclofen in nonstroke patients with severe spasticity utilized the health care use pattern of study patients during the year before pump implantation as a control.54 Despite the high cost of the pump, its surgical implantation, and its refill requirement, an initial overall net savings in medical costs was reported. This cost reduction was primarily ascribed to a reduced length of hospital stay after admission for any reason.54

Despite limitations, several studies have documented improved quality of life, reduced spasms, improved function, and decreased pain after initiation of intrathecal baclofen in patients with spinal cord injury or multiple sclerosis.35,55,56 Given the high costs of treatment related to falls and fractures, pharmacologic regimens that lower the risk of these phenomena due to reduced AEs should be considered. The interpretation of the cost analyses cited herein is limited, given that studies were unable to measure the indirect costs associated with falls in this patient group.  

Conclusion

The high costs of treatment associated with the morbidity and mortality related to falls and fractures is likely to increase exponentially in the years to come given the growing aging population. Post-stroke patients suffering from spasticity are potentially at increased risk for falling. Treatment of spasticity may thus be an increasingly important factor in the prevention of falls. It is crucial that a new paradigm be considered in the management of these patients. Systemic medication regimens should be considered in light of their potential for increasing the risk of falling due to AEs such as sedation or gait disturbance. It is likely that government agencies such as Medicare and private payers will be extremely interested in newer therapies if they can potentially offset the primary cost drivers in their growing health care expenditures related to falls. Many national patient organizations, such as the National Stroke Association, are producing educational materials that focus on the management of spasticity and the prevention of falls, and emphasize the need to avoid medications that have been shown to increase risk of falls. Focal treatments, such as botulinum toxin type A, are associated with a low risk of AEs and have been shown to be efficacious in the treatment of post-stroke spasticity. Systemic oral agents may be appropriate as adjuncts to focal treatments when lower doses can be used safely. Conclusions should be tempered, however, by the lack of specific data regarding antispasticity treatments and the risk of falls in the post-stroke population.

Dr. Esquenazi has indicated that he has received educational grants from Allergan, Inc., Procter & Gamble, and Medtronic, Inc.