Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis. Report of the Guideline Development Subcommittee of the American Academy of Neurology

Cannabinoids

Cannabinoid Practice Recommendations

Clinicians might offer oral cannabis extract (OCE) to patients with multiple sclerosis (MS) to reduce patient-reported symptoms of spasticity and pain (excluding central neuropathic pain) (Level A) and might counsel patients that this symptomatic benefit is possibly maintained for 1 year (Level C), although OCE is probably ineffective for improving objective spasticity measures (short-term) or tremor (Level B).

Clinicians might offer tetrahydrocannabinol (THC) to patients with MS to reduce patient-reported symptoms of spasticity and pain (excluding central neuropathic pain) (Level B). Clinicians might counsel patients that this symptomatic benefit is possibly maintained for 1 year (Level C), although THC is probably ineffective for improving objective spasticity measures (short-term) or tremor (Level B).

Clinicians might offer Sativex oromucosal cannabinoid spray (nabiximols), where available, to reduce symptoms of spasticity, pain, or urinary frequency, although it is probably ineffective for improving objective spasticity measures or number of urinary incontinence episodes (Level B).

Clinicians might choose not to offer Sativex oromucosal cannabinoid spray to reduce MS-related tremor (Level C).

Data are inadequate to support or refute use of the following in MS (Level U):

1. OCE/THC for bladder urge incontinence and overall symptoms
2. Synthetic THC (Marinol) for central neuropathic pain
3. Sativex oromucosal cannabinoid spray for overall bladder symptoms, anxiety symptoms/sleep problems, cognitive symptoms, quality of life (QOL), and fatigue
4. Smoked cannabis for spasticity, pain, balance/posture, and cognition

Data are inadequate to determine the abuse potential or effect on psychopathologic symptoms of Sativex cannabinoid spray (Level U).

Clinical Context

The cannabinoid studies have limitations that physicians and patients must be aware of. Most studies were of short duration (6 to 15 weeks). Another limitation was the potential for central side effects to unmask patients to treatment assignment — a concern with regard to all masked trials involving treatments with prominent side effects. It is also important to recognize that the Ashworth scale used for objective measurement may be insensitive to spasticity changes. These factors may contribute to the discordant effects of cannabinoids on subjective and objective spasticity measures.

Ginkgo Biloba (GB)

GB Practice Recommendations

Clinicians might counsel patients with MS that GB is established as ineffective for improving cognitive function (Level A).

Clinicians might counsel patients with MS that GB is possibly effective for reducing fatigue (Level C).

Clinical Context

GB and other supplements are not U.S. Food and Drug Administration (FDA) regulated. Their quality control may play a role in their effectiveness and adverse effect (AE) risk. Moreover, interactions of supplements with other medications, especially disease-modifying therapies for MS, are a clinical concern.

Low-Fat Diet with Omega-3 Fatty Acid Supplementation (Omega-3)

Omega-3 Practice Recommendation

Clinicians might counsel patients that a low-fat diet with fish oil supplementation is probably ineffective for reducing relapses, disability, or magnetic resonance imaging (MRI) lesions, or for improving fatigue or QOL in MS (Level B).

Lofepramine

Lofepramine Practice Recommendation

Clinicians might counsel patients with MS that lofepramine plus L-phenylalanine with vitamin B₁₂ (Cari Loder regimen) is possibly ineffective for treating disability, symptoms, depression, or fatigue (Level C).

Reflexology

Reflexology Practice Recommendation

Clinicians might counsel patients with MS that reflexology is possibly effective for reducing paresthesia (Level C).

Bee Venom

Bee Venom Practice Recommendation

Clinicians might counsel patients with MS that bee sting therapy is possibly ineffective for reducing relapses, disability, fatigue, total MRI lesion burden, new gadolinium-enhancing lesion volume, or health-related quality of life (HRQOL) (Level C).

Clinical Context

Bee stings can be associated with anaphylactic reaction and possible death.

Magnetic Therapy

Magnetic Therapy Practice Recommendation

Clinicians might counsel patients with MS that magnetic therapy is probably effective for reducing fatigue (Level B) and probably ineffective for reducing depression (Level B).

Other CAM Therapies Practice Recommendation

Clinicians should counsel patients with MS that the safety and efficacy of other reviewed CAM, or the interaction of CAM with disease-modifying therapies for MS, are unknown (Level U).

Definitions:

Classification of Evidence for Therapeutic Interventions

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a-e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b-e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)

Level C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

Cannabinoids

Cannabinoid Practice Recommendations

Clinicians might offer oral cannabis extract (OCE) to patients with multiple sclerosis (MS) to reduce patient-reported symptoms of spasticity and pain (excluding central neuropathic pain) (Level A) and might counsel patients that this symptomatic benefit is possibly maintained for 1 year (Level C), although OCE is probably ineffective for improving objective spasticity measures (short-term) or tremor (Level B).

Clinicians might offer tetrahydrocannabinol (THC) to patients with MS to reduce patient-reported symptoms of spasticity and pain (excluding central neuropathic pain) (Level B). Clinicians might counsel patients that this symptomatic benefit is possibly maintained for 1 year (Level C), although THC is probably ineffective for improving objective spasticity measures (short-term) or tremor (Level B).

Clinicians might offer Sativex oromucosal cannabinoid spray (nabiximols), where available, to reduce symptoms of spasticity, pain, or urinary frequency, although it is probably ineffective for improving objective spasticity measures or number of urinary incontinence episodes (Level B).

Clinicians might choose not to offer Sativex oromucosal cannabinoid spray to reduce MS-related tremor (Level C).

Data are inadequate to support or refute use of the following in MS (Level U):

1. OCE/THC for bladder urge incontinence and overall symptoms
2. Synthetic THC (Marinol) for central neuropathic pain
3. Sativex oromucosal cannabinoid spray for overall bladder symptoms, anxiety symptoms/sleep problems, cognitive symptoms, quality of life (QOL), and fatigue
4. Smoked cannabis for spasticity, pain, balance/posture, and cognition

Data are inadequate to determine the abuse potential or effect on psychopathologic symptoms of Sativex cannabinoid spray (Level U).

Clinical Context

The cannabinoid studies have limitations that physicians and patients must be aware of. Most studies were of short duration (6 to 15 weeks). Another limitation was the potential for central side effects to unmask patients to treatment assignment — a concern with regard to all masked trials involving treatments with prominent side effects. It is also important to recognize that the Ashworth scale used for objective measurement may be insensitive to spasticity changes. These factors may contribute to the discordant effects of cannabinoids on subjective and objective spasticity measures.

Ginkgo Biloba (GB)

GB Practice Recommendations

Clinicians might counsel patients with MS that GB is established as ineffective for improving cognitive function (Level A).

Clinicians might counsel patients with MS that GB is possibly effective for reducing fatigue (Level C).

Clinical Context

GB and other supplements are not U.S. Food and Drug Administration (FDA) regulated. Their quality control may play a role in their effectiveness and adverse effect (AE) risk. Moreover, interactions of supplements with other medications, especially disease-modifying therapies for MS, are a clinical concern.

Low-Fat Diet with Omega-3 Fatty Acid Supplementation (Omega-3)

Omega-3 Practice Recommendation

Clinicians might counsel patients that a low-fat diet with fish oil supplementation is probably ineffective for reducing relapses, disability, or magnetic resonance imaging (MRI) lesions, or for improving fatigue or QOL in MS (Level B).

Lofepramine

Lofepramine Practice Recommendation

Clinicians might counsel patients with MS that lofepramine plus L-phenylalanine with vitamin B₁₂ (Cari Loder regimen) is possibly ineffective for treating disability, symptoms, depression, or fatigue (Level C).

Reflexology

Reflexology Practice Recommendation

Clinicians might counsel patients with MS that reflexology is possibly effective for reducing paresthesia (Level C).

Bee Venom

Bee Venom Practice Recommendation

Clinicians might counsel patients with MS that bee sting therapy is possibly ineffective for reducing relapses, disability, fatigue, total MRI lesion burden, new gadolinium-enhancing lesion volume, or health-related quality of life (HRQOL) (Level C).

Clinical Context

Bee stings can be associated with anaphylactic reaction and possible death.

Magnetic Therapy

Magnetic Therapy Practice Recommendation

Clinicians might counsel patients with MS that magnetic therapy is probably effective for reducing fatigue (Level B) and probably ineffective for reducing depression (Level B).

Other CAM Therapies Practice Recommendation

Clinicians should counsel patients with MS that the safety and efficacy of other reviewed CAM, or the interaction of CAM with disease-modifying therapies for MS, are unknown (Level U).

Definitions:

Classification of Evidence for Therapeutic Interventions

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a-e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b-e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)

Level C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

Cannabinoids

Cannabinoid Practice Recommendations

Clinicians might offer oral cannabis extract (OCE) to patients with multiple sclerosis (MS) to reduce patient-reported symptoms of spasticity and pain (excluding central neuropathic pain) (Level A) and might counsel patients that this symptomatic benefit is possibly maintained for 1 year (Level C), although OCE is probably ineffective for improving objective spasticity measures (short-term) or tremor (Level B).

Clinicians might offer tetrahydrocannabinol (THC) to patients with MS to reduce patient-reported symptoms of spasticity and pain (excluding central neuropathic pain) (Level B). Clinicians might counsel patients that this symptomatic benefit is possibly maintained for 1 year (Level C), although THC is probably ineffective for improving objective spasticity measures (short-term) or tremor (Level B).

Clinicians might offer Sativex oromucosal cannabinoid spray (nabiximols), where available, to reduce symptoms of spasticity, pain, or urinary frequency, although it is probably ineffective for improving objective spasticity measures or number of urinary incontinence episodes (Level B).

Clinicians might choose not to offer Sativex oromucosal cannabinoid spray to reduce MS-related tremor (Level C).

Data are inadequate to support or refute use of the following in MS (Level U):

1. OCE/THC for bladder urge incontinence and overall symptoms
2. Synthetic THC (Marinol) for central neuropathic pain
3. Sativex oromucosal cannabinoid spray for overall bladder symptoms, anxiety symptoms/sleep problems, cognitive symptoms, quality of life (QOL), and fatigue
4. Smoked cannabis for spasticity, pain, balance/posture, and cognition

Data are inadequate to determine the abuse potential or effect on psychopathologic symptoms of Sativex cannabinoid spray (Level U).

Clinical Context

The cannabinoid studies have limitations that physicians and patients must be aware of. Most studies were of short duration (6 to 15 weeks). Another limitation was the potential for central side effects to unmask patients to treatment assignment — a concern with regard to all masked trials involving treatments with prominent side effects. It is also important to recognize that the Ashworth scale used for objective measurement may be insensitive to spasticity changes. These factors may contribute to the discordant effects of cannabinoids on subjective and objective spasticity measures.

Ginkgo Biloba (GB)

GB Practice Recommendations

Clinicians might counsel patients with MS that GB is established as ineffective for improving cognitive function (Level A).

Clinicians might counsel patients with MS that GB is possibly effective for reducing fatigue (Level C).

Clinical Context

GB and other supplements are not U.S. Food and Drug Administration (FDA) regulated. Their quality control may play a role in their effectiveness and adverse effect (AE) risk. Moreover, interactions of supplements with other medications, especially disease-modifying therapies for MS, are a clinical concern.

Low-Fat Diet with Omega-3 Fatty Acid Supplementation (Omega-3)

Omega-3 Practice Recommendation

Clinicians might counsel patients that a low-fat diet with fish oil supplementation is probably ineffective for reducing relapses, disability, or magnetic resonance imaging (MRI) lesions, or for improving fatigue or QOL in MS (Level B).

Lofepramine

Lofepramine Practice Recommendation

Clinicians might counsel patients with MS that lofepramine plus L-phenylalanine with vitamin B₁₂ (Cari Loder regimen) is possibly ineffective for treating disability, symptoms, depression, or fatigue (Level C).

Reflexology

Reflexology Practice Recommendation

Clinicians might counsel patients with MS that reflexology is possibly effective for reducing paresthesia (Level C).

Bee Venom

Bee Venom Practice Recommendation

Clinicians might counsel patients with MS that bee sting therapy is possibly ineffective for reducing relapses, disability, fatigue, total MRI lesion burden, new gadolinium-enhancing lesion volume, or health-related quality of life (HRQOL) (Level C).

Clinical Context

Bee stings can be associated with anaphylactic reaction and possible death.

Magnetic Therapy

Magnetic Therapy Practice Recommendation

Clinicians might counsel patients with MS that magnetic therapy is probably effective for reducing fatigue (Level B) and probably ineffective for reducing depression (Level B).

Other CAM Therapies Practice Recommendation

Clinicians should counsel patients with MS that the safety and efficacy of other reviewed CAM, or the interaction of CAM with disease-modifying therapies for MS, are unknown (Level U).

Definitions:

Classification of Evidence for Therapeutic Interventions

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a-e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b-e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II or III criteria including consensus or expert opinion.

*Note that numbers 1-3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Classification of Recommendations

Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

Level B = Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)

Level C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).