SUBSTANCE USE DSM

• Larger , Longer
• Control - Loss of control
• Time : Getting, using, recovering
•
• T
• W
• C
•
• Functional impairment : work , home , school
• Giving up : social / recreational / occupational
•
• Use despite relationship problems
• Use despite harm - danger
• Use despite harm - physical or psychological problems

Mild : 2-3
Mod: 4-5
Sev: six or more

Easy to conceptualise:

- Duration, quantity
- Control
- Salience (Time : Getting, using, recovering)

-T
-W
-C

- Functional impairment - 2 types : A) work/home/school B) Loss of interest

- Harm : Use despite harm - 3 types A) Relationship B) Danger C) Health -
Physical or psychological

Antidepressant mechanism of action:

Monoamine hypothesis - depression is caused by depletion of monoamines

(DA,NE or HT).

Neurotransmitters (NT) receptor hypothesis : depression is caused by

upregulation of NT receptors.

Antidepressants acutely block one or more of the presynaptic transporter for

these monoamines (Dopamine transporter, Norephrine transporter or
serotonin transporter)
Acute increase in neurotransmitters (NT) levels cause adaptive changes in
neurotransmitter receptor sensitivity in delayed time course. —> adaptive
down regulation and desensitisation of postsynaptic NT receptors.

Adaptive changes —> alteration of gene expression : turning off the synthesis
of NT receptors and increasing the synthesis of neurotrophic factors like
BDNF.

Major class:

SSRI - HT selective
SNRI - HT and NE
NDRI - NE and DA
Selective NRI - NE
SARI - Serotonin antagonist / reuptake inhibitor
MAOI - monoamine oxidase inhibitor
TCA
NaSSA

SNRI - HT and NE:

• Venlafaxine ,
• Des-Venlafaxine (relatively greater NET inhibition than Venlafaxine)
• Duloxetine

NDRI : Bupropion

NaSSA:
Also known as serotonin norepinephrine disinhibition (SNDI)

Mirtazapine
Noradrenergic and specific serotonorgic antidepressant

Primary action through blocking Alfa 2 receptor : raises both serotonin and
norepinephrine levels

The endocannabinoid system consists of endogenous cannabinoids

(endocannabinoids), cannabinoid receptors and the synthetic and degrading
enzymes responsible for synthesis and degradation of endocannabinoids

--> The first endocannabinoid identified was arachidonoyl ethanolamide

(anandamide)
--> second endocannabinoid identified was 2-arachidonoyl glycerol (2-AG)

Although endocannabinoids clearly activate CB1 and CB2 receptors, they

also interact with other GPCRs and ion channels.
Receptors:

CB1 receptors are abundant in the cerebellum, basal ganglia, hippocampus

and dorsal primary afferent spinal cord regions, which is why cannabinoids
influence functions such as memory processing, pain regulation and motor
control. In the brain stem, the concentration of cannabinoids is low, which may
be related to why cannabis use is not associated with sudden death due to
depressed respiration, for example.

The CB2 receptors are mainly found on white blood cells, in the tonsils and
in the spleen. The immune cells also express CB1, although there are fewer
of them than CB2. In the immune system, one important function of the
cannabinoid receptors is the regulation of cytokine release. Stimulation of the
CB1 receptor produces marijuana-like effects on the psyche and circulation,
while no such effect is seen when the CB2 receptor is activated. Therefore,
selective CB2 receptor agonists have become increasingly popular subjects of
research for their potential anti-inflammatory and anti-cancer effects.

The cannabis plant has two main subspecies, Cannabis indica and Cannabis
sativa, and they can be differentiated by their different physical
characteristics. Indica-dominant strains are short plants with broad, dark
green leaves and have higher cannabidiol content than the sativa plants in
which THC content is higher. Sativa-dominant strains are usually taller and
have thin leaves with a pale green colour. Due to its higher THC content,
C. sativa is the preferred choice by users.

It is a complex plant with about 426 chemical entities, of which more than 60
are cannabinoid compounds . The four major compounds are d-9-THC, CBD,
d-8-THC and cannabinol, which have been most researched .

BZD:

Short acting
T1/2 upto 5 hr

ATOM : Alprazolam , Triazolam, Oxazepam, Midazolam

Intermediate acting

T1/2 - 5 to 24 hr
Temazepam, Lorazepam , Clonazepam

Long acting Benzodiazepines

T1/2 > 24 hr
Clorazepate, Clordiazepoxide, Diazepam , Flurazepam

Benzodiazepines not metabolized by the liver and safe to use in liver failure

Oxazepam, Temazepam, Lorazepam

MECHANISM OF ACTION

BZDs act as positive allosteric modulators on the gamma amino butyric acid
(GABA)-A receptor. The GABA-A receptor is a ligand-gated chloride-selective
ion channel.

GABA is the most common neurotransmitter in the central nervous system,

found in high concentrations in the cortex and limbic system.

GABA is inhibitory in nature and thus reduces the excitability of neurons.

GABA produces a calming effect on the brain.2

Allosteric modulators are a group of substances that bind to a receptor to

change that receptor's response to stimuli.
The site to which endogenous agonists bind to is named the orthosteric site.
Modulators don't bind to this site. They bind to any other suitable sites, which
are named allosteric sites.
Chronic pain and mental health disorders

Chronic pain and mental health disorders are common in the general
population, and epidemiological studies suggest that a bidirectional
relationship exists between these 2 conditions. The observations from
functional imaging studies suggest that this bidirectional relationship is due in
part to shared neural mechanisms.

Within the broader biopsychosocial model of pain, the fear avoidance model
explains how behavioral factors affect the temporal course of chronic pain and
provides the framework for an array of efficacious behavioral interventions
including cognitive behavioral therapy, acceptance-based therapies, and
multidisciplinary pain rehabilitation.

Garcia-Larrea and Peyron7 have proposed a pain matrix composed of 3

tiers, or levels, of interrelated neural activity

1 -- “first-order” processing refers to nociceptive activation of the

spinothalamic tract, which comprises neurons in the dorsal horn of the spinal
cord with axonal projections terminating in the posterior thalamus.

2 -- attentional and cognitive modulation : Nociceptive stimuli are then

posited to undergo “second-order” processing in the anterior cingulate
cortex (ACC), insula, prefrontal cortex (PFC), and posterior parietal cortex.
As a result, nociceptive stimuli are consciously perceived, subjected to
attentional and cognitive modulation, and transformed into somatic, or
“vegetative,” responses. (ACC, PFC,PPC,I)

3 -- reappraisal and descending control : The perception and modulation of

pain is further affected, or “reappraised,” by the emotional context of the
stimuli and further individualized by psychological factors that together
coalesce in memory formation. Neural structures implicated in this final “third-
order” process include the oribitofrontal, perigenual ACC, and anterolateral
PFC regions. Brain regions comprising the second and third tiers interact with
various descending tracts in the spinal cord, resulting in either inhibitory or
facilitatory modulation of incoming nociceptive stimuli in a process termed
descending control. (OFC, PG ACC, AL PFC)

-- The frequent co-occurrence of chronic pain and depression reflects the

shared risks that exist between these 2 conditions

-- A bidirectional relationship exists between chronic spinal pain and

depression, in which spinal pain is a risk factor for depression and depression
is a risk factor for spinal pain. These studies also suggest that the bidirectional
relationship is affected, in part, by a dose-response phenomenon between
pain intensity and the severity of depressive symptoms

-- Various chronic pain conditions, including fibromyalgia, abdominal pain, and

low back pain, have been associated with functional imaging alterations in
brain regions responsible for processing emotional stimuli, including the ACC
and PFC.63-66 Conversely, in adults with depression, emotional processing
in the insula has been reported to shift toward an insular region associated
with processing pain stimuli in healthy individuals.

-- Similar to depression, a bidirectional relationship exists between chronic

pain and anxiety. This is particularly evident in individuals with migraine
headache. In population-based studies, individuals with migraine are 2 to 3
times more likely to be diagnosed with GAD, panic disorder, agoraphobia, or
PTSD than individuals without migraine.40 Conversely, individuals with
anxiety disorders are twice as likely to develop migraine headache than
individuals without anxiety disorders.
EVIDENCE BASED MEDCINE

Takeaway points:

- Interventions available are not supported by robust evidence base

- Poor understanding of pain as a condition
- Methodological problems : how we define severity and improvement,
placebo response, bias
- Challenges in individualising evidence base in clinical care
- Challenges in predicting treatment response

There is a short but active history of evidence-based pain medicine, and the
Cochrane Library has more than 288 systematic reviews of primary
randomized controlled trials.

WHAT DO WE KNOW?

We know that pain is ultimately a private mental event, as is any perception,

emotion, or cognition. We know that this private and subjective experience is
also social, expressed, and so experienced in a common language, in
behaviors subject to common rules, and in a form evolved over time to
promote the protection of self and others.

Pain not associated with a progressive disease, such as cancer, can often
persist past a presumed healing time and can become a condition in and of
itself. Such persistent pain is not only a symptom of another disease but a
disease in its own right. Finally, we know that pain is difficult to treat.

From both a clinical and an evidence synthesis perspective, it is sensible to

consider interventions for acute pain and chronic pain separately.

ACUTE PAIN:

The first is that very few of the systematic reviews of interventions for acute
pain can be said to show clinically significant differences at a meaningful
level: typically, a 1-point change on a 10-point scale. The second fact is that in
the pooled analysis, a review of systematic reviews in which up to 50 000
patients’ responses were analyzed, the very best responses in the field of
pain management provide a number needed to treat of only slightly less than
two.6
Thus, only slightly more than 50% of patients randomized to treatment or
alternative achieve at least 50% pain reduction after four to six hours who
would not have done so with placebo.
CHRONIC PAIN:

The CDSR records 91 reviews of chronic noncancer pain. Although most of

the reviews look at pharmacological interventions for neuropathic pain, also
included are persistent pain in torture survivors, acupuncture patients, and
those who have experienced interventions for reducing opioid use for chronic
noncancer pain.
- There is no evidence to support the use of high dose (200 mg or more
morphine equivalent daily) opioids in chronic noncancer pain.
- The review of acupuncture for neuropathic pain concludes that because of
the limited data there is insufficient evidence to reduce uncertainty.
- A review of gabapentin in neuropathic pain suggested that after shingles,
three in 10 people had their pain reduced by 50% with gabapentin (1200 mg
daily or more), whereas two in 10 had the same response with
placebo. Although side effects were more common with gabapentin

- Physiotherapy for CRPS : A systematic review failed to find any trials of

appropriate quality, although physiotherapy maintains its role as the mainstay
of treatment of this condition.

- A systematic review of the use of botulinum toxin for myofascial pain

syndrome concluded that there was “inconclusive” evidence to support its use
and “more high quality randomised controlled trials . . . need to be conducted.

- Amitriptyline for neuropathic pain: A systematic review stated, “There was no

supportive unbiased evidence for a beneficial effect.”13

- A review of opioids for pain associated with rheumatoid arthritis suggested

there was “limited evidence” for the efficacy of weak opioids up to six
weeks but no evidence beyond six weeks and no evidence for the use of
strong opioids

- Prevention of chronic pain after surgery : a systematic review of

pharmacotherapies suggested that better designed trials were needed and
that there was no current evidence to support the use of a multitude of
interventions.

- A review looking at psychological interventions for improving physical

function, reducing pain, and reducing low mood in fibromyalgia suggested
they may be effective but stated the “quality of the evidence is low.

WHAT WE DON'T KNOW ?

- We do not yet know how to capture pain complexity as a multifaceted

experience. Our theories and practices remain largely unidimensional and
biological. The greatest challenge will be to develop a common language of
pain and a pain treatment that captures pain’s complexity without sacrificing
action.
- Unidimensional scores, such as a zero to 10 pain rating, may not be telling
us what we think they do. These scores focus on the felt experience, and not
on the consequences (behaviourally, relationally, or socially) of the pain. In
some cases, altering the felt experience with relief from pain, may allow a
return to pre-pain activity. In other cases, it may not. Because
the psychosocial components are ignored.

- We do not yet know how to tailor our evidence to the individual or even to
subclasses of individuals. Most of our evidence is based on average effects
for average patients. Most patients are not average in their response to any
intervention.

- What is unknown often is how to predict who will respond well to a particular
intervention. Clinically, it would be helpful to establish starting, stopping, and
switching rules for any pain management plan.

- Unfortunately, the concept of an individual trial of medication is rarely done

well in clinical practice.

- At a public health level, we encourage an approach to treatment provision on

the basis of treatment pathways that consider the evidence but that also seek
to reduce an individual’s unnecessary exposure to ineffective interventions
and a rapid assessment and switch to alternatives.

- Finally, rarely discussed but critically important is the role of the comparator
in trials that make up the evidence base. From the sham TENS
(transcutaneous electrical nerve stimulation) machine to the waiting list control
to the fake pill or injection, comparator (often placebo) responses in trials are
often uncomfortably high. How researchers impute missing data, but they are
also higher responses than in other fields of medicine. This has led to an
interest in the potential therapeutic use of placebo. Properly framed, high
placebo effects show that we should work harder to understand the
psychosocial context of how pain is experienced and expressed.

NEXT GENERATION EVIDENCE-BASED MEDICINE

- Innovations in both big (high volume population) and small (high-volume

individual) data may revolutionise the information we have to make
personalised decisions.
- Cochrane itself is turning toward increased mining of individual patient
data from the trials we have to greater decision support by translation of
evidence into guidelines and to greater use of artificial intelligence in the
updating and rapid production of evidence.

- Prioritising new reviews and updates, translating review outputs into

practice, and developing new methodologies for the review of non–
randomized controlled trial primary sources.

- Developing methods of network metaanalysis that would allow an evaluation

of indirect comparisons in the use of novel trial design such as enriched
enrolment,22 in a more idiographic focus on individual change in complex
interventions, and in outcomes in low-income countries.
Botulinum toxin

Botulinum toxin, often referred to as Botox, is a neurotoxin produced by the

bacterium Clostridium botulinum. It works by disrupting the normal functioning
of nerve cells and muscles.

-- Acetylcholine Release Inhibition: Normally, when a nerve cell wants to send

a signal to a muscle to contract, it releases a neurotransmitter called
acetylcholine at the neuromuscular junction (the point where the nerve and
muscle meet). Acetylcholine acts as a messenger, transmitting the signal from
the nerve to the muscle.

-- Botulinum Toxin Binding: Botulinum toxin binds to the nerve endings at the
neuromuscular junction, specifically the nerve endings that release
acetylcholine. This binding is highly selective and occurs in a specific and
controlled manner.

-- Inhibition of Acetylcholine Release: Once bound to the nerve endings,

botulinum toxin prevents the release of acetylcholine from these nerve cells.
This inhibition occurs by interfering with the normal process of vesicle fusion
and neurotransmitter release.

-- Muscle Paralysis: As a result of the reduced acetylcholine release, the

muscle does not receive the signal to contract effectively. This leads to
muscle paralysis or weakness in the affected area.

-- Temporary Effect: The effects of botulinum toxin are temporary because

nerve cells can regenerate, and new nerve endings can form over time. This
is why Botox treatments need to be repeated periodically to maintain the
desired effect.

-- In medical and cosmetic applications, Botox is used to reduce muscle

activity temporarily. It is commonly used to treat conditions such as muscle
spasms, excessive sweating (hyperhidrosis), and wrinkles caused by muscle
contractions in the face.

-- The toxin's ability to inhibit acetylcholine release makes it an effective tool

for relaxing muscles and alleviating various medical and cosmetic concerns.
MIGRAINE

1. Muscle Relaxation: Botox is a neurotoxin that can temporarily paralyze or

weaken muscles when injected. In the context of migraines, it's thought that
Botox injections can relax the muscles in the head, neck, and shoulder region.
This muscle relaxation may reduce muscle tension and spasms that can
contribute to migraine headaches.

2. Inhibition of Pain Signaling: Botox may interfere with the transmission of

pain signals. It is known to inhibit the release of neurotransmitters
(acetylcholine) at the neuromuscular junction, which is where nerves and
muscles communicate. By reducing the release of certain neurotransmitters,
Botox may dampen the pain signals that contribute to migraine pain.

3. Anti-Inflammatory Effects: Chronic inflammation may play a role in migraine

development. Some research suggests that Botox could have anti-
inflammatory properties, which may help reduce inflammation in the tissues
surrounding nerves involved in migraines.

4. Nerve Signal Damping: Botox may affect sensory nerves, reducing their
sensitivity to pain signals. This could potentially decrease the perception of
pain associated with migraines.

5. Modulation of Trigeminal Nerve Activity: Migraines often involve the

trigeminal nerve, which plays a crucial role in transmitting pain signals from
the head and face. Botox may modulate the activity of the trigeminal nerve,
further reducing migraine pain.

CLINICAL GUIDELINE

A clinical guideline, also known as a clinical practice guideline or medical

guideline, is a systematically developed document or set of
recommendations designed to assist healthcare professionals in making
informed decisions about the care and treatment of patients. Clinical
guidelines are based on a synthesis of the best available scientific evidence,
expert consensus, and clinical expertise. They provide evidence-based
guidance on various aspects of patient care, including the diagnosis,
treatment, prevention, and management of medical conditions and healthcare
practices.

Developing clinical guidelines is a meticulous and collaborative process that

aims to provide evidence-based recommendations for healthcare practitioners
and improve patient care. It requires ongoing commitment to quality,
transparency, and continuous improvement. Developing clinical guidelines is
a complex process that involves rigorous research, expert consensus, and
careful consideration of the available evidence. Here are the steps typically
involved in developing clinical guidelines:
1 - Define the Scope and Purpose
2 - Constitute a Guideline Development Group (multidisciplinary team of
experts in the field, including clinicians, researchers, methodologists, and
patient representatives)
3 - Systematic Review of the Evidence
4 - Formulate Clinical Recommendations
5 - Grading the Recommendations (strong vs weak)
6 - External Review and Feedback (external stakeholders, including
healthcare professionals, patients, and relevant organizations)
7 - Finalize the Guideline
8 - Peer Review and Endorsement
9 - Dissemination and Implementation
10 - Update and Maintenance
11 - Monitoring and Evaluation
12 - Documentation and Transparency

Problematic substance use refers to patterns of using psychoactive

substances, including alcohol and drugs, in a way that can lead to various
negative consequences and harm to an individual's physical health, mental
well-being, relationships, and overall quality of life. It is characterized by
behaviors and circumstances related to substance use that may be
concerning or problematic, even if they do not meet the criteria for a formal
diagnosis of a substance use disorder.

Chronic pain and problematic substance use are two frequently co-occurring
and significant health problems in the United States. On its own, chronic pain
(e.g., pain lasting longer than 3–6 months and persisting beyond the healing
of an initial injury or disease) is very complicated to treat and associated with
a multitude of negative health problems and functional issues. In an effort to
alleviate pain, many individuals turn to substances such as alcohol, tobacco,
and opioids , leading to a higher prevalence of comorbid chronic pain and
substance use concerns .

The resulting interaction between chronic pain and substance use is complex.
For instance, although frequent use of substances can have short-term
analgesic impacts, pain is often exacerbated during subsequent abstinence
periods , and repeated opioid misuse can also induce hyperalgesia .

When chronic pain prompts self-medication through substances, this in turn

contributes to escalating problematic substance use and poorer pain-
treatment outcomes, resulting in a positive feedback loop maintaining both
issues.
Even in the absence of a formal substance use diagnosis, individuals with
chronic pain can experience greater levels of pain due to problematic
substance use or drinking and drug use that does not meet full substance use
disorder criteria but is linked to personal distress, physical health issues, or
legal or social concerns.

Major Depression
Key Requirements:

• Duration: Symptoms must be present for at least 2 weeks.

• Minimum Symptoms: 5 or more symptoms, with at least one being
(1) depressed mood or (2) loss of interest or pleasure.

Symptoms:

1. Depressed mood most of the day, nearly every day.

2. Loss of interest or pleasure in most activities.
3. Significant weight change or appetite disturbance.
4. Insomnia or hypersomnia.
5. Psychomotor agitation or retardation (observable by others).
6. Fatigue or loss of energy.
7. Feelings of worthlessness or excessive guilt.
8. Diminished ability to think or concentrate, or indecisiveness.
9. Recurrent thoughts of death or suicidal ideation.

Additional Criteria:

• Functional Impairment: Symptoms cause significant distress or

impairment in daily life.
• Exclusions: Symptoms not due to substance use, medical
conditions, or other mental disorders.
• No History of Mania: No history of manic or hypomanic episodes.
DSM-5 Criteria for Generalized Anxiety Disorder (GAD)

Key Requirements:

• Duration: Excessive anxiety and worry occurring more days than

not for at least 6 months.
• Focus: Worry is difficult to control and can be about various events
or activities (e.g., work, school).

Symptoms:

• Minimum Symptoms: 3 or more of the following (only 1 required in

children):
1. Restlessness or feeling keyed up or on edge.
2. Easily fatigued.
3. Difficulty concentrating or mind going blank.
4. Irritability.
5. Muscle tension.
6. Sleep disturbance (difficulty falling or staying asleep, or restless,
unsatisfying sleep).

Additional Criteria:

• Functional Impairment: Anxiety and worry cause significant distress

or impairment in social, occupational, or other important areas of functioning.
• Exclusions: Symptoms are not due to the physiological effects of a
substance, medical condition, or another mental disorder.

DSM-5 Criteria for Somatic Symptom Disorder

Key Requirements:

• Duration: Symptoms must be present for at least 6 months.

• Core Symptom: One or more somatic symptoms (e.g., pain, fatigue)
that are distressing or result in significant disruption of daily life.

Symptoms:

• Excessive Thoughts, Feelings, or Behaviors related to the somatic

symptoms, with at least one of the following:
1. Disproportionate and persistent thoughts about the seriousness of
the symptoms.
2. Persistently high level of anxiety about health or symptoms.
3. Excessive time and energy devoted to these symptoms or health
concerns.

Additional Criteria:

• Functional Impairment: The condition causes significant distress or

impairment in social, occupational, or other important areas of functioning.
 • Exclusions: Symptoms are not better explained by another medical
condition or mental disorder.

DSM-5 Criteria for Substance Use Disorder

Key Requirements:

• Duration: Problematic pattern of substance use leading to

significant impairment or distress, occurring within a 12-month period.
• Substances: Can apply to various substances (e.g., alcohol,
opioids, stimulants, etc.).

Symptoms:

• Minimum Symptoms: 2 or more of the following within a 12-month

period:
1. Larger amounts or longer use than intended.
2. Persistent desire or unsuccessful efforts to cut down or control use.
3. Great deal of time spent obtaining, using, or recovering from the
substance.
4. Craving or strong desire to use the substance.
5. Failure to fulfill major obligations at work, school, or home due to
use.
6. Continued use despite persistent or recurrent social or
interpersonal problems.
7. Giving up or reducing important activities because of use.
8. Use in physically hazardous situations.
9. Continued use despite knowing it’s causing physical or
psychological problems.
10. Tolerance: Needing more of the substance to achieve the same
effect or experiencing reduced effect with the same amount.
11. Withdrawal: Experiencing withdrawal symptoms or using the
substance to avoid withdrawal.

Severity Specifiers:

• Mild: 2-3 symptoms.

• Moderate: 4-5 symptoms.
• Severe: 6 or more symptoms.

Comparison of DSM-5 and ICD-11 Criteria for Substance Use Disorder

1. Terminology:

• DSM-5: Uses “Substance Use Disorder” (SUD) with graded severity

(mild, moderate, severe).
• ICD-11: Uses “Disorders due to Substance Use,” distinguishing
between “Harmful Use” and “Dependence Syndrome.”

2. Diagnostic Approach:
 • DSM-5: Combines substance abuse and dependence into a single
disorder with 11 criteria; diagnosis based on having at least 2 symptoms.
• ICD-11: Separates “Harmful Use” (health damage) and
“Dependence Syndrome” (3+ symptoms of dependence).

3. Severity Grading:

• DSM-5: Graded by the number of symptoms:

• Mild: 2-3 symptoms.
• Moderate: 4-5 symptoms.
• Severe: 6+ symptoms.
• ICD-11: No explicit grading within categories but distinguishes
harmful use from dependence.

4. Focus:

• DSM-5: Emphasizes impact on social, occupational, and daily

functioning.
• ICD-11: Focuses on health consequences and dependence
development.

5. Global Use:

• DSM-5: Primarily used in the U.S. with detailed criteria.

• ICD-11: Used globally, broader, and designed for diverse
healthcare settings.

In summary,
• The DSM-5 offers a more detailed, symptom-based, and graded
approach to diagnosing substance use disorders, emphasizing the impact on
daily functioning and recognizing different levels of severity.
• The ICD-11 takes a broader, more categorical approach, focusing
on the harmful effects and the development of dependence, and is designed
for wider global application. It distinguishes between harmful use and
dependence, rather than combining them into a single disorder with varying
severity as the DSM-5 does.